Mutations in COL4A1 have been reported in schizencephaly and porencephaly combined with microbleeds or calcifications, often associated with ocular and renal abnormalities, myopathy, elevated ...creatine kinase levels and haemolytic anaemia. In this study, we aimed to clarify the phenotypic spectrum of COL4A1/A2 mutations in the context of cortical malformations that include schizencephaly, polymicrogyria and/or heterotopia.
We screened for COL4A1/A2 mutations in 9 patients with schizencephaly and/or polymicrogyria suspected to be caused by vascular disruption and leading to a cerebral haemorrhagic ischaemic event. These included 6 cases with asymmetrical or unilateral schizencephaly and/or polymicrogyria and 3 cases with bilateral schizencephaly.
One de novo missense COL4A1 mutation (c.3715 G > A, p.(Gly1239Arg)) and two COL4A2 mutations were found, respectively in one familial case (c.4129G > A, p.(Gly1377Arg)) and one sporadic patient (c.1776+1G > A). In three other cases, COL4A1 variants of unknown significance were identified. None of our patients demonstrated neuromuscular or hematological anomalies. Brain malformations included a combination of schizencephaly, mainly asymmetrical, with porencephaly or ventriculomegaly (3/3 mutated patients). We did not observe microbleeds or microcalcifications in any of our cases, hence we do not believe that they represent a distinctive feature of COL4A1/A2 mutations.
Our study further emphasizes the need to search for both COL4A1 and COL4A2 mutations in children presenting with uni- or bilateral polymicrogyria with schizencephaly, even in the absence of intracranial microbleeds, calcification or associated systemic features.
We report four patients from two families who presented attacks of childhood‐onset episodic ataxia associated with pathogenic mutations in the FGF14 gene. Attacks were triggered by fever, lasted ...several days, and had variable frequencies. Nystagmus and/or postural tremor and/or learning disabilities were noticed in individuals harboring FGF14 mutation with or without episodic ataxia. These cases and literature data delineate the FGF14‐mutation‐related episodic ataxia phenotype: wide range of age at onset (from childhood to adulthood), variable durations and frequencies, triggering factors including fever, and association to chronic symptoms. We propose to add FGF14‐related episodic ataxia to the list of primary episodic ataxia as Episodic Ataxia type 9.
The aim of the study was to redefine the phenotype of Allan–Herndon–Dudley syndrome (AHDS), which is caused by mutations in the SLC16A2 gene that encodes the brain transporter of thyroid hormones. ...Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty‐four males aged 11 months to 29 years had a mutation in SLC16A2, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (n=12), seizures (n=7), and pneumopathies (n=5) were the most severe complications. This study extends the phenotypic spectrum of AHDS to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro‐orthopaedic, pulmonary, and epileptic complications.
What this paper adds
Mild intellectual disability is associated with SLC16A2 mutations.
A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients.
Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
What this paper adds
Mild intellectual disability is associated with SLC16A2 mutations.
A thyroid hormone profile with a free T3/T4 ratio higher than 0.75 can help diagnose patients.
Patients with SLC16A2 mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
Pyridoxine-dependent epilepsy (PDE) is a recessive genetic disease characterized by epileptic encephalopathy with therapeutic response to pharmacological doses of pyridoxine and resistance to ...anti-epileptic treatments. The recent discovery in 2006 of the genetic defect antiquitin (ALDH7A1, OMIM #266100) has helped to understand the underlying mechanism, which is the accumulation of neurotoxic intermediates in the lysine catabolic pathway. The goal of the new therapeutic approach, termed triple therapy (TT) (pyridoxine, lysine-restricted diet and arginine supplementation), is to improve epilepsy control and neurocognitive development in patients with PDE. We present the 3-year treatment outcome for a child with PDE on pyridoxine treatment (started at age 5 months), lysine-restricted diet (started at age 17 months) and arginine supplementation therapy (started at age 19 months). The TT was well-tolerated with good compliance. No adverse events were reported. We observed a neurodevelopmental improvement, significantly fewer seizures, and a reduction of pipecolic acid (PA) as a biomarker of the illness. Our results show an improving clinical evolution, supporting and extending previous studies reporting efficacy of TT.
Objective
N‐methyl‐d‐aspartate (NMDA) receptors are expressed at synaptic sites, where they mediate fast excitatory neurotransmission. NMDA receptors are critical to brain development and cognitive ...function. Natural variants to the GRIN1 gene, which encodes the obligatory GluN1 subunit of the NMDA receptor, are associated with severe neurological disorders that include epilepsy, intellectual disability, and developmental delay. Here, we investigated the pathogenicity of three missense variants to the GRIN1 gene, p. Ile148Val (GluN1‐3bI481V), p.Ala666Ser (GluN1‐3bA666S), and p.Tyr668His (GluN1‐3bY668H).
Methods
Wild‐type and variant‐containing NMDA receptors were expressed in HEK293 cells and primary hippocampal neurons. Patch‐clamp electrophysiology and pharmacology were used to profile the functional properties of the receptors. Receptor surface expression was evaluated using fluorescently tagged receptors and microscopy.
Results
Our data demonstrate that the GluN1(I481V) variant is inhibited by the open pore blockers ketamine and memantine with reduce potency but otherwise has little effect on receptor function. By contrast, the other two variants exhibit gain‐of‐function molecular phenotypes. Glycine sensitivity was enhanced in receptors containing the GluN1(A666S) variant and the potency of pore block by memantine and ketamine was reduced, whereas that for MK‐801 was increased. The most pronounced functional deficits, however, were found in receptors containing the GluN1(Y668H) variant. GluN1(Y668H)/2A receptors showed impaired surface expression, were more sensitive to glycine and glutamate by an order of magnitude, and exhibited impaired block by extracellular magnesium ions, memantine, ketamine, and MK‐801. These variant receptors were also activated by either glutamate or glycine alone. Single‐receptor recordings revealed that this receptor variant opened to several conductance levels and activated more frequently than wild‐type GluN1/2A receptors.
Significance
Our study reveals a critical functional locus of the receptor (GluN1Y668) that couples receptor gating to ion channel conductance, which when mutated may be associated with neurological disorder.
MCT8 deficiency is a rare genetic leukoencephalopathy caused by a defect of thyroid hormone transport across cell membranes, particularly through blood brain barrier and into neural cells. It is ...characterized by a complex neurological presentation, signs of peripheral thyrotoxicosis and cerebral hypothyroidism. Movement disorders (MDs) have been frequently mentioned in this condition, but not systematically studied.
Each patient recruited was video-recorded during a routine outpatient visit according to a predefined protocol. The presence and the type of MDs were evaluated. The type of MD was blindly scored by two child neurologists experts in inherited white matter diseases and in MD. Dystonia was scored according to Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). When more than one MD was present, the predominant one was scored.
27 patients were included through a multicenter collaboration. In many cases we saw a combination of different MDs. Hypokinesia was present in 25/27 patients and was the predominant MD in 19. It was often associated with hypomimia and global hypotonia. Dystonia was observed in 25/27 patients, however, in a minority of cases (5) it was deemed the predominant MD. In eleven patients, exaggerated startle reactions and/or other paroxysmal non-epileptic events were observed.
MDs are frequent clinical features of MCT8 deficiency, possibly related to the important role of thyroid hormones in brain development and functioning of normal dopaminergic circuits of the basal ganglia. Dystonia is common, but usually mild to moderate in severity, while hypokinesia was the predominant MD in the majority of patients.
•Movement disorders are frequent in patients with MCT8 deficiency.•Dystonia is common, but moderate or mild in severity- Hypokinesia is common and severe, and it appeared to contribute much more to the overall functional disability burden.•Paroxysmal movement disorders may be present, mimic in some case epileptic seizures.
The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMSs), a clinically and ...genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.
The 10q26 subtelomeric microdeletion syndrome is a rare and clinically heterogeneous disorder. The precise relationships between the causative genes and the phenotype are unclear.
We report two new ...cases of 860 kb deletion of 10q26.2 identified by array CGH in a fetus with intrauterine growth retardation and his mother. The deleted region encompassed only four coding genes, DOCK1, INSYN2, NPS and FOX12. The proband had dysmorphic facies characterized by a high forehead, malformed ears, a prominent nose, and retrognathia. He had bilateral club feet, clinodactily and mild psychomotor retardation. His mother had a short stature, microcephaly, a long face with a high forehead and bitemporal narrowing, arched and sparse eyebrows, strabismus, prominent nose and chin, a thin upper lip and large protruding ears, and mild intellectual disability.
This study presents the smallest 10q26.2 deletion so far identified, which further refines the minimal critical region associated with the 10q26 microdeletion syndrome. It focuses on three genes potentially responsible for the phenotype: DOCK1, which is the major candidate gene, and INSYN2 and NPS, which could be involved in cognitive functions.
The aim of the study was to redefine the phenotype of Allan–Herndon–Dudley syndrome (
AHDS
), which is caused by mutations in the
SLC
16A2
gene that encodes the brain transporter of thyroid hormones. ...Clinical phenotypes, brain imaging, thyroid hormone profiles, and genetic data were compared to the existing literature. Twenty‐four males aged 11 months to 29 years had a mutation in
SLC
16A2
, including 12 novel mutations and five previously described mutations. Sixteen patients presented with profound developmental delay, three had severe intellectual disability with poor language and walking with an aid, four had moderate intellectual disability with language and walking abilities, and one had mild intellectual disability with hypotonia. Overall, eight had learned to walk, all had hypotonia, 17 had spasticity, 18 had dystonia, 12 had choreoathetosis, 19 had hypomyelination, and 10 had brain atrophy. Kyphoscoliosis (
n
=12), seizures (
n
=7), and pneumopathies (
n
=5) were the most severe complications. This study extends the phenotypic spectrum of
AHDS
to a mild intellectual disability with hypotonia. Developmental delay, hypotonia, hypomyelination, and thyroid hormone profile help to diagnose patients. Clinical course depends on initial severity, with stable acquisition after infancy; this may be adversely affected by neuro‐orthopaedic, pulmonary, and epileptic complications.
What this paper adds
Mild intellectual disability is associated with
SLC16A2
mutations.
A thyroid hormone profile with a free T
3
/T
4
ratio higher than 0.75 can help diagnose patients.
Patients with
SLC16A2
mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
What this paper adds
Mild intellectual disability is associated with
SLC16A2
mutations.
A thyroid hormone profile with a free T
3
/T
4
ratio higher than 0.75 can help diagnose patients.
Patients with
SLC16A2
mutations present a broad spectrum of neurological phenotypes that are also observed in other hypomyelinating disorders.
Axial hypotonia is a consistent feature of Allan–Herndon–Dudley syndrome and leads to specific complications.
Importance
There is to date limited evidence that revascularization strategies are associated with improved functional outcome in children with acute ischemic stroke (AIS).
Objectives
To report ...clinical outcomes and provide estimates of revascularization strategy safety and efficacy profiles of intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) in children with AIS.
Design, Setting, and Participants
The KidClot multicenter nationwide cohort study retrospectively collected data of children (neonates excluded) with AIS and recanalization treatment between January 1, 2015, and May 31, 2018. Data analysis was performed from January 1, 2015, to May 31, 2019.
Exposure
IVT and/or EVT.
Main Outcomes and Measures
Primary outcome was day 90 favorable outcome (modified Rankin Scale mRs 0-2, with 0 indicating no symptoms and 6 indicating death). Secondary end points included 1-year favorable outcome (mRs, 0-2), mortality, and symptomatic intracerebral hemorrhage. Other measures included the Pediatric National Institutes of Health Stroke Scale (pedNIHSS), with pedNIHSS 0 indicating no symptoms, 1 to 4 corresponding to a minor stroke, 5 to 15 corresponding to a mild stroke, greater than 15 to 20: severe stroke, and the adult Alberta Stroke Program Early CT Score (ASPECTS), which provides segmental assessment of the vascular territory, with 1 point deducted from the initial score of 10 for every region involved (from 10 no lesion to 0 maximum lesions).
Results
Overall, 68 children were included in 30 centers (IVT n = 44; EVT n = 40; 44 boys 64.7%; median IQR age, 11 4-16 years; anterior circulation involvement, 57 83.8%). Median (IQR) pedNIHSS score at admission was 13 (7-19), higher in the EVT group at 16 (IQR, 10-20) vs 9 (6-17) in the IVT only group (
P
< .01). Median time from stroke onset to imaging was higher in the EVT group at 3 hours and 7 minutes (IQR, 2 hours and 3 minutes to 6 hours and 24 minutes) vs 2 hours and 39 minutes (IQR, 1 hour and 51 minutes to 4 hours and 13 minutes) (
P
= .04). Median admission ASPECTS score was 8 (IQR, 6-9). The main stroke etiologies were cardioembolic (21 30.9%) and focal cerebral arteriopathy (17 25.0%). Median (IQR) time from stroke onset to IVT was 3 hours and 30 minutes (IQR, 2 hours and 33 minutes to 4 hours and 28 minutes). In the EVT group, the rate of postprocedure successful reperfusion (≥modified Treatment in Cerebral Infarction 2b) was 80.0% (32 of 40). Persistent proximal arterial stenosis was more frequent in focal cerebral arteriopathy (
P
< .01). Death occurred in 3 patients (4.4%). Median pedNIHSS reduction at 24 hours was 4 (IQR, 0-9) points. Intracerebral hemorrhage occurred in 4 patients and symptomatic intracerebral hemorrhage occurred in 1 patient, all in the EVT group. The median mRS was 2 (IQR, 0-3) at day 90 and 1 (IQR, 0-2) at 1 year, which was not significantly different between EVT and IVT only groups, although different in initial severity.
Conclusions and Relevance
The findings of this cohort study suggest that use of EVT and/or IVT is safe in children with AIS.
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