OBJECTIVE:To report 14 patients with immune-mediated relapsing symptoms post–herpes simplex encephalitis (HSE) and to compare the clinical and immunologic features of the teenage and adult group with ...those of young children.
METHODS:Prospective observational study of patients diagnosed between June 2013 and February 2015. Immunologic techniques have been reported previously.
RESULTS:Among the teenage and adult group (8 patients, median age 40 years, range 13–69; 5 male), 3 had an acute symptom presentation suggesting a viral relapse, and 5 a presentation contiguous with HSE suggesting a recrudescence of previous deficits. Seven patients developed severe psychiatric/behavioral symptoms disrupting all social interactions, and one refractory status epilepticus. Blepharospasm occurred in one patient. Five patients had CSF antibodies against NMDA receptor (NMDAR) and 3 against unknown neuronal cell surface proteins. In 5/6 patients, the brain MRI showed new areas of contrast enhancement that decreased after immunotherapy and clinical improvement. Immunotherapy was useful in 7/7 patients, sometimes with impressive recoveries, returning to their baseline HSE residual deficits. Compared with the 6 younger children (median age 13 months, range 6–20, all with NMDAR antibodies), the teenagers and adults were less likely to develop choreoathetosis (0/8 vs 6/6, p < 0.01) and decreased level of consciousness (2/8 vs 6/6, p < 0.01) and had longer delays in diagnosis and treatment (interval relapse/antibody testing 85 days, range 17–296, vs 4 days, range 0–33, p = 0.037).
CONCLUSION:In teenagers and adults, the immune-mediated relapsing syndrome post-HSE is different from that known in young children as choreoathetosis post-HSE and is underrecognized. Prompt diagnosis is important because immunotherapy can be highly effective.
The short pre-M1 helix within the S1–M1 linker (also referred to as the pre-M1 linker) between the agonist-binding domain (ABD, S1) and the M1 transmembrane helix of the NMDA receptor (NMDAR) is ...devoid of missense variants within the healthy population but is a locus for de novo pathogenic variants associated with neurological disorders. Several de novo variants within this helix have been identified in patients presenting early in life with intellectual disability, developmental delay, and/or epilepsy. In this study, we evaluated functional properties for twenty variants within the pre-M1 linker in
GRIN1
,
GRIN2A
, and
GRIN2B
genes, including six novel missense variants. The effects of pre-M1 variants on agonist potency, sensitivity to endogenous allosteric modulators, response time course, channel open probability, and surface expression were assessed. Our data indicated that virtually all of the variants evaluated altered channel function, and multiple variants had profound functional consequences, which may contribute to the neurological conditions in the patients harboring the variants in this region. These data strongly suggest that the residues within the pre-M1 helix play a key role in channel gating and are highly intolerant to genetic variation.
X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy characterized by profound skeletal muscle weakness, respiratory distress, and motor dysfunction. However, ...pathology is not limited to muscle and can be associated with life-threatening hepatic peliosis. Hepatobiliary disease has been reported in up to 17% of XLMTM patients but has not been extensively characterized. We report on five XLMTM patients who experienced intrahepatic cholestasis in their disease natural history, illustrating the need to further investigate these manifestations. These patients shared presentations that included pruritus, hypertransaminemia, and hyperbilirubinemia with normal gamma-glutamyl transferase, following infection or vaccination. Three patients who had genetic testing showed no evidence of genetic mutations associated with familial cholestasis. In one patient, progression to cirrhotic, decompensated liver disease occurred. Further investigations into the molecular pathomechanism underpinning these clinical observations in XLMTM patients will be important for informing patient care.
GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial ...(NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.
Background
αB‐crystallin is a promiscuous protein involved in numerous cell functions. Mutations in CRYAB have been found in patients with different pathological phenotypes that are not properly ...understood. Patients can present different diseases like cataracts, muscle weakness, myopathy, cardiomyopathy, respiratory insufficiency or dysphagia, but also a variable combination of these pathologies has been found. These mutations can show either autosomal dominant or recessive mode of inheritance and variable penetrance and expressivity. This is the first report of congenital cataracts and myopathy described in childhood due to a CRYAB mutation with autosomal dominant mode of inheritance.
Methods
The whole exome sequence was subjected to phenotype‐driven analysis and a novel variant in CRYAB was detected: c.514delG, p.(Ala172ProfsTer14). The mutation was located in the C‐terminal domain of the protein, which is essential for chaperone activity. The deduced protein was analyzed searching for alterations of the relevant physico‐chemical properties described for this domain. A muscle biopsy was also tested for CRYAB with immunohistochemical and histoenzymatic techniques.
Results
CRYAB displayed a mild immunoreactivity in the subsarcolemmal compartment with no pathological sarcoplasmic accumulation. It agrees with an alteration of the physico‐chemical properties predicted for the C‐terminal domain: hydrophobicity, stiffness, and isomerization.
Conclusions
The described mutation leads to elongation of the protein at the carboxi‐terminal domain (CTD) with altered properties, which are essential for solubility and activity. It suggests that can be the cause of the severe conditions observed in this patient.
The isolation of DNA and whole exome sequencing led us to discover a novel mutation in a CRYAB which causes cataracts, myopathies and other conditions observed in the proband. The predicted altered physico‐chemical properties of the C‐terminal are related with low activity and low solubility. This new condition agrees with the muscle biopsy where the cell is depleted and the mutated protein is found attached to the membrane cell.
Abstract Rett Syndrome (RS; MIM_312750) is a severe and progressive neurodevelopmental disorder affecting principally females. Mutations in X-Linked MECP2 gene (methyl CpG-binding protein 2; ...MIM_300005) have been reported as being the major cause of RS. Mutations in this gene have been described as cause of wide spectrum of neurological disorders and mental retardation in males. In some cases, mutations in MECP2 in males produce clinical picture similar to RS. Here we report the identification of the novel truncating mutation Y120X in a 4-year-old child with atypical RS phenotype. Chromosome analysis showed a normal karyotype, and blood DNA and tissue DNA analysis reveal a mosaic for the mutation. Patient’s mother DNA analysis showed that this is a de novo mutation, that has never been described before in any female or male case of RS.
Key Clinical Message
Despite co‐segregation of two different genetic neurological disorders within a family is rare, clinicians should take into consideration this possibility in patients presenting ...with unusual complex phenotypes or with unexpected electrophysiological findings. Here, we report a Spanish 11‐month‐old patient with spinal muscular atrophy type 2 and Charcot‐Marie‐Tooth 1A.
Despite co‐segregation of two different genetic neurological disorders within a family is rare, clinicians should take into consideration this possibility in patients presenting with unusual complex phenotypes or with unexpected electrophysiological findings. Here, we report a Spanish 11‐month‐old patient with spinal muscular atrophy type 2 and Charcot‐Marie‐Tooth 1A.
INTRODUCTIONWest syndrome (WS) is an age-dependent epileptic encephalopathy in which the prognosis varies according to the, not always identified, underlying origin. OBJECTIVESTo define the profile ...of cryptogenic (a least studied isolated sub-group) WS, in Spain. To study its outcome, response to different treatments, and to establish prognostic factors. PATIENTS AND METHODSThe study included a review of the medical records of 16 patients diagnosed with cryptogenic WS during the period, 2000-2015. The mean follow-up time was 6.6 years, with a minimum of 2 years. RESULTSThe large majority (11/16) were male. The mean age at onset was 6 months, and 6/16 had a family history of idiopathic epilepsy. The first line treatment with vigabatrin had an electrical-clinical response in 5/16 patients, with the remaining cases responding to adrenocorticotropic hormone (ACTH). Almost half (44%) of the patients progressed to other types of epilepsy, with no difference between those treated with vigabatrin or ACTH. A greater number of adverse effects were obtained with ACTH, with no retinal involvement being observed with vigabatrin. The aetiological cause was found in 2/16. Being female, late onset, and early control of the hypsarrhythmia, were factors of a good prognosis. CONCLUSIONSThe overall prognosis of cryptogenic WS was more serious than expected. Although the incidence of Lennox-Gastaut syndrome was low, the progression to focal epilepsy was the most common, with it appearing within the first 2 years of the diagnosis. The initial response to vigabatrin was lower than expected, but the long-term result was comparable to ACTH.
Herpes simplex encephalitis can trigger autoimmune encephalitis that leads to neurological worsening. We aimed to assess the frequency, symptoms, risk factors, and outcomes of this complication.
We ...did a prospective observational study and retrospective analysis. In the prospective observational part of this study, we included patients with herpes simplex encephalitis diagnosed by neurologists, paediatricians, or infectious disease specialists in 19 secondary and tertiary Spanish centres (Cohort A). Outpatient follow-up was at 2, 6, and 12 months from onset of herpes simplex encephalitis. We studied another group of patients retrospectively, when they developed autoimmune encephalitis after herpes simplex encephalitis (Cohort B). We compared demographics and clinical features of patients who developed autoimmune encephalitis with those who did not, and in patients who developed autoimmune encephalitis we compared these features by age group (patients ≤4 years compared with patients >4 years). We also used multivariable binary logistic regression models to assess risk factors for autoimmune encephalitis after herpes simplex encephalitis.
Between Jan 1, 2014, and Oct 31, 2017, 54 patients with herpes simplex encephalitis were recruited to Cohort A, and 51 were included in the analysis (median age 50 years IQR 5–68). At onset of herpes simplex encephalitis, none of the 51 patients had antibodies to neuronal antigens; during follow-up, 14 (27%) patients developed autoimmune encephalitis and all 14 (100%) had neuronal antibodies (nine 64% had NMDA receptor NMDAR antibodies and five 36% had other antibodies) at or before onset of symptoms. The other 37 patients did not develop autoimmune encephalitis, although 11 (30%) developed antibodies (n=3 to NMDAR, n=8 to unknown antigens; p<0·001). Antibody detection within 3 weeks of herpes simplex encephalitis was a risk factor for autoimmune encephalitis (odds ratio OR 11·5, 95% CI 2·7–48·8; p<0·001). Between Oct 7, 2011, and Oct 31, 2017, there were 48 patients in Cohort B with new-onset or worsening neurological symptoms not caused by herpes simplex virus reactivation (median age 8·8 years IQR 1·1–44·2; n=27 male); 44 (92%) patients had antibody-confirmed autoimmune encephalitis (34 had NMDAR antibodies and ten had other antibodies). In both cohorts (n=58 patients with antibody-confirmed autoimmune encephalitis), patients older than 4 years frequently presented with psychosis (18 58% of 31; younger children not assessable). Compared with patients older than 4 years, patients aged 4 years or younger (n=27) were more likely to have shorter intervals between onset of herpes simplex encephalitis and onset of autoimmune encephalitis (median 26 days IQR 24–32 vs 43 days 25–54; p=0·0073), choreoathetosis (27 100% of 27 vs 0 of 31; p<0·001), decreased level of consciousness (26 96% of 27 vs seven 23% of 31; p<0·001), NMDAR antibodies (24 89% of 27 vs 19 61% of 31; p=0·033), and worse outcome at 1 year (median modified Rankin Scale 4 IQR 4–4 vs 2 2–3; p<0·0010; seizures 12 63% of 19 vs three 13% of 23; p=0·001).
The results of our prospective study show that autoimmune encephalitis occurred in 27% of patients with herpes simplex encephalitis. It was associated with development of neuronal antibodies and usually presented within 2 months after treatment of herpes simplex encephalitis; the symptoms were age-dependent, and the neurological outcome was worse in young children. Prompt diagnosis is important because patients, primarily those older than 4 years, can respond to immunotherapy.
Mutua Madrileña Foundation, Fondation de l'Université de Lausanne et Centre Hospitalier Universitaire Vaudois, Instituto Carlos III, CIBERER, National Institutes of Health, Generalitat de Catalunya, Fundació CELLEX.
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