Genotype-phenotype correlation in CLCN4-related developmental and epileptic encephalopathy.

CLCN4-related disorder is a rare X-linked neurodevelopmental condition with a pathogenic mechanism yet to be elucidated. CLCN4 encodes the vesicular 2Cl-/H+ exchanger ClC-4, and CLCN4 pathogenic variants frequently result in altered ClC-4 transport activity. The precise cellular and molecular function of ClC-4 remains unknown; however, together with ClC-3, ClC-4 is thought to have a role in the ion homeostasis of endosomes and intracellular trafficking. We reviewed our research database for patients with CLCN4 variants and epilepsy, and performed thorough phenotyping. We examined the functional properties of the variants in mammalian cells using patch-clamp electrophysiology, protein biochemistry, and confocal fluorescence microscopy. Three male patients with developmental and epileptic encephalopathy were identified, with differing phenotypes. Patients #1 and #2 had normal growth parameters and normal-appearing brains on MRI, while patient #3 had microcephaly, microsomia, complete agenesis of the corpus callosum and cerebellar and brainstem hypoplasia. The p.(Gly342Arg) variant of patient #1 significantly impaired ClC-4's heterodimerization capability with ClC-3 and suppressed anion currents. The p.(Ile549Leu) variant of patient #2 and p.(Asp89Asn) variant of patient #3 both shift the voltage dependency of transport activation by 20 mV to more hyperpolarizing potentials, relative to the wild-type, with p.(Asp89Asn) favouring higher transport activity. We concluded that p.(Gly342Arg) carried by patient #1 and the p.(Ile549Leu) expressed by patient #2 impair ClC-4 transport function, while the p.(Asp89Asn) variant results in a gain-of-transport function; all three variants result in epilepsy and global developmental impairment, but with differences in epilepsy presentation, growth parameters, and presence or absence of brain malformations.

mTOR Pathway Somatic Pathogenic Variants in Focal Malformations of Cortical Development: Novel Variants, Topographic Mapping, and Clinical Outcomes.

Background and Objectives: Somatic and germline pathogenic variants in genes of the mammalian target of rapamycin (mTOR) signaling pathway are a common mechanism underlying a subset of focal malformations of cortical development (FMCDs) referred to as mTORopathies, which include focal cortical dysplasia (FCD) type II, subtypes of polymicrogyria, and hemimegalencephaly. Our objective is to screen resected FMCD specimens with mTORopathy features on histology for causal somatic variants in mTOR pathway genes, describe novel pathogenic variants, and examine the variant distribution in relation to neuroimaging, histopathologic classification, and clinical outcomes. Methods: We performed ultra-deep sequencing using a custom HaloPlexHS Target Enrichment kit in DNA from 21 resected fresh-frozen histologically confirmed FCD type II, tuberous sclerosis complex, or hemimegalencephaly specimens. We mapped the variant alternative allele frequency (AAF) across the resected brain using targeted ultra-deep sequencing in multiple formalin-fixed paraffin-embedded tissue blocks. We also functionally validated 2 candidate somatic MTOR variants and performed targeted RNA sequencing to validate a splicing defect associated with a novel DEPDC5 variant. Results: We identified causal mTOR pathway gene variants in 66.7% (14/21) of patients, of which 13 were somatic with AAF ranging between 0.6% and 12.0%. Moreover, the AAF did not predict balloon cell presence. Favorable seizure outcomes were associated with genetically clear resection borders. Individuals in whom a causal somatic variant was undetected had excellent postsurgical outcomes. In addition, we demonstrate pathogenicity of the novel c.4373_4375dupATG and candidate c.7499T>A MTOR variants in vitro. We also identified a novel germline aberrant splice site variant in DEPDC5 (c.2802-1G>C). Discussion: The AAF of somatic pathogenic variants correlated with the topographic distribution, histopathology, and postsurgical outcomes. Moreover, cortical regions with absent histologic FCD features had negligible or undetectable pathogenic variant loads. By contrast, specimens with frank histologic abnormalities had detectable pathogenic variant loads, which raises important questions as to whether there is a tolerable variant threshold and whether surgical margins should be clean, as performed in tumor resections. In addition, we describe 2 novel pathogenic variants, expanding the mTORopathy genetic spectrum. Although most pathogenic somatic variants are located at mutation hotspots, screening the full-coding gene sequence remains necessary in a subset of patients.

Longitudinal Characterization of the Clinical Course of Intermediate-Severe Salla Disease.

BACKGROUND: Biallelic pathogenic variants in SLC17A5 cause three forms of free sialic acid storage disease categorized based on severity from least to most severe: Salla disease, intermediate-severe Salla disease, and infantile free sialic acid storage disease. Intermediate-severe Salla disease is the most recently described form. Here, we report a longitudinal characterization of intermediate-severe Salla disease progression in two sisters carrying the following biallelic variants in SLC17A5: c.406A>G (p.Lys136Glu) and c.819+1G>A. METHODS: A retrospective review of medical records was performed. A developmental questionnaire was completed to obtain further clinical information. For functional characterization of the predicted splice site variant, RNA was extracted from patient blood samples and sequenced. RESULTS: Disease onset occurred within the first six months of life in both patients. Early childhood development was delayed with achievement of some milestones followed by a developmental plateau in late childhood. After this, both patients began a slow and progressive neurological regression in adolescence. Functional studies confirmed the pathogenicity of the c.819+1G>A variant, resulting in a frameshift and deletion of exon 6. CONCLUSIONS: We present a detailed study describing the clinical course of intermediate-severe Salla disease with over 15 to 20 years of evolution and demonstrate the pathogenicity of the c.819+1G>A splice site variant.

The Experience of Parents of Children With Genetically Determined Leukoencephalopathies With the Health Care System: A Qualitative Study.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. We sought to gain a better understanding of their experience with the public health care system in Quebec, Canada, to obtain suggestions for improving their services, and to identify modifiable factors to improve their quality of life. We conducted interviews with 13 parents. Data was analyzed thematically. Five themes were identified: challenges of the diagnostic odyssey, limited access to services, excessive parental responsibilities, positive relationships with health care professionals as a facilitator of care, and benefits of a specialized leukodystrophy clinic. Parents felt like waiting for the diagnosis was extremely stressful, and they expressed their need for transparency during this period. They identified multiple gaps and barriers in the health care system, which burdened them with many responsibilities. Parents emphasized the importance of a positive relationship with their child's health care professionals. They also felt grateful for being followed at a specialized clinic as it improved the quality of care received.

Randomized placebo-controlled crossover trial of memantine in children with epileptic encephalopathy.

Memantine is an N-methyl-D-aspartate receptor antagonist, approved for dementia treatment. There is limited evidence of memantine showing benefit for paediatric neurodevelopmental phenotypes, but no randomized placebo-controlled trials in children with developmental and epileptic encephalopathy. In this randomized double-blind placebo-controlled crossover trial (Trial registration: https://clinicaltrials.gov/ct2/show/NCT03779672), patients with developmental and epileptic encephalopathy received memantine and placebo, each for a 6-week period separated by a 2-week washout phase. Electroencephalography, seizure diary, patient caregivers' global impression, serum inflammatory markers and neuropsychological evaluation were performed at baseline and after each treatment phase. The primary outcome measure was classification as a 'responder', defined as ≥2 of: >50% seizure frequency reduction, electroencephalography improvement, caregiver clinical impression improvement or clear neuropsychological testing improvement. Thirty-one patients (13 females) enrolled. Two patients withdrew prior to initiating medication and two (twins) had to be removed from analysis. Of the remaining 27 patients, nine (33%) were classified as responders to memantine versus two (7%) in the placebo group (P < 0.02). Electroencephalography improvement was seen in eight patients on memantine compared to two on placebo (P < 0.04). Seizure improvement was observed in eight patients on memantine and two on placebo (P < 0.04). Caregivers reported overall clinical improvement in 10 patients on memantine compared to seven on placebo (not significant). Statistical analysis of neuropsychological evaluation suggested improvements in symptoms of attention-deficit hyperactivity disorder and autism. Memantine is a safe and effective treatment for children with developmental and epileptic encephalopathy, having the potential to improve both seizure control and cognitive function.

Spontaneous Resolution of Drug-Resistant Epilepsy in Patients with Sturge-Weber Syndrome.

Introduction: Sturge-Weber syndrome (SWS) is often associated with drug resistant epilepsy. The literature is unclear as to how often these patients can be weaned off of antiepileptic drugs (AEDs) to become seizure-free. Case Description: We describe two patients with SWS. After initial treatment with various AEDs, breakthrough seizures still occurred. However, after periods with no seizure activity, they were weaned off of their medications. They have been off for 4 and 3 years and seizure-free for 13 and 12 years, respectively. No surgical procedure was necessary. Conclusion: We hypothesize that spontaneous involution or pathological disconnection of the vascular malformations might underly the patients' recovery. The initial aggressive therapy, close follow-up, choice of AEDs, or natural evolution of the disease may have played a role in their recovery. Therefore, in patients with SWS and lesional structural epilepsy, medication freedom is possible and invasive management options including surgery should be discussed carefully.

Diagnostic utility of specific abnormal EEG patterns in children for determining epilepsy phenotype and presence of structural brain abnormalities.

Objective: Estimate sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of EEG findings: centrotemporal spikes, photoparoxysmal response, asymmetric photic driving, and asymmetric sleep spindles, for epilepsy phenotype and presence of structural brain abnormalities. Methods: In this case-control study we reviewed children referred for EEG over a 4-year period, with at least one of centrotemporal spikes, photoparoxysmal response, asymmetric photic driving, or asymmetric sleep spindles. This cohort was analyzed in combination with a research database of pediatric patients with seizures. Results: Centrotemporal spikes had 100% sensitivity for childhood epilepsy with centrotemporal spikes or atypical childhood epilepsy with centrotemporal spikes, but lower specificity (70%) and PPV (58%). Photoparoxysmal response had high specificity (92%) and NPV (92%) for genetic generalized epilepsy. Asymmetric photic driving had low sensitivity for structural brain abnormalities (17%), with specificity 80%. In contrast, asymmetric sleep spindles had much higher sensitivity and specificity, 44% and 97%, respectively. Conclusions: Although centrotemporal spikes are classically associated with childhood epilepsy with centrotemporal spikes, these discharges are seen in other conditions. Photoparoxysmal response is highly indicative of a genetic generalized epilepsy, though may be seen in other epilepsy phenotypes. Relative attenuation of sleep spindles is a more reliable indicator of structural brain malformation than asymmetric photic driving. Significance: The quantitative diagnostic utility of EEG findings should be considered when incorporating these results into clinical decision-making.

Novel biallelic variants in NRROS associated with a lethal microgliopathy, brain calcifications, and neurodegeneration.

Negative regulator of reactive oxygen species (NRROS) is a leucine-rich repeat protein expressed by microglia and perivascular macrophages. To date, 9 individuals have been reported with biallelic NRROS variants. Here, we report one individual with a severe neurodegenerative phenotype in which exome sequencing identified 2 novel variants in NRROS, a missense variant (c.185T>C, p.Leu62Pro) and a premature stop codon (c.310C>T, p.Gln104Ter). Pathological examination revealed both extensive grey and white matter involvement, dystrophic calcifications, and infiltration of foamy macrophages. This is the first reported case of NRROS variants with a mitochondrial ultrastructure abnormality noted on electron microscopy analysis of post-mortem tissue.

Experience of Parents of Children with Genetically Determined Leukoencephalopathies Regarding the Adapted Health Care Services During the COVID-19 Pandemic.

Parents of children with genetically determined leukoencephalopathies play a major role in their children's health care. Because of the COVID-19 pandemic, many health care services were suspended, delayed or delivered remotely with telemedicine. We sought to explore the experience of parents of children with genetically determined leukoencephalopathies during the pandemic given the adapted health care services. We conducted semistructured interviews with 13 parents of 13 affected children. Three main themes were identified using thematic analysis: perceived impact of COVID-19 on health care services, benefits and challenges of telemedicine, and expectations of health care after the pandemic. Parents perceived a loss/delay in health care services while having a positive response to telemedicine. Parents wished telemedicine would remain in their care after the pandemic. This is the first study assessing the impact of COVID-19 on health care services in this population. Our results suggest that parents experience a higher level of stress owing to the shortage of services and the children's vulnerability.

Hirayama Disease in a Patient with a History of Late-Onset Symptomatic Vein of Galen Aneurysmal Malformation.

INTRODUCTION: The purpose of this report is to present a rare case of Hirayama disease (HD) in a patient with a history of late-onset symptomatic vein of Galen aneurysmal malformation (VGAM). This report may provide new insights into the pathophysiology of HD, a rare disorder consisting of insidious onset of unilateral weakness and atrophy of the forearm and intrinsic hand muscles. These symptoms are believed to result from cervical myelopathy affecting the anterior horn cells due to abnormal compressive forces on the spinal cord from adjacent anatomical structures (i.e., dura and/or epidural veins), but this has not been proven. VGAM is a rare congenital cerebral vascular malformation, consisting of high-flow arteriovenous shunting between a persistent median prosencephalic vein and arterial feeders, which most frequently presents in the early neonatal period with congestive heart failure. CASE PRESENTATION: We report the case of an otherwise healthy boy who presented with heart failure due to VGAM at 7 years and subsequently presented at 14 years with left-sided HD. His cervical MRI with neck flexion revealed enlarged epidural veins at the C5-C6 spinal level with anterior, leftward displacement of the posterior dura and spinal cord as well as left hemicord flattening and/or atrophy at this level. He underwent successful surgical treatment by C5-C6-C7 osteoplastic laminotomies and tenting and expansile autologous duraplasty, during which enlarged, engorged epidural veins were confirmed and coagulated. This halted the progression of his left hand weakness and atrophy and allowed significant functional improvement. Postoperative catheter angiogram showed no anatomical connection between the persistent VGAM and the engorged epidural veins, and genetic testing revealed no genetic predisposition of vascular malformations. DISCUSSION/CONCLUSION: In this patient, a combined surgical technique was performed that included epidural venous plexus coagulation with posterior autologous duraplasty and dural fixation using tenting sutures. This combined approach led to a favorable clinical and radiographic outcome with no complications or limitations and has not been previously proposed in the literature, to our knowledge. Although not completely ruled out, we found no angiographic connection or genetic predisposition to suggest there is a pathophysiological link between HD and VGAM.

A Novel De Novo Variant in DYNC1H1 Causes Spinal Muscular Atrophy Lower Extremity Predominant in Identical Twins: A Case Report.

Mutations in DYNC1H1 have been shown to cause spinal muscular atrophy lower extremity predominant type 1 (SMALED1), an autosomal dominant genetic neuromuscular disorder characterized by degeneration of spinal cord motor neurons resulting in muscle weakness. Here, we describe monozygotic twins, one with a more severe upper motor neuron phenotype as a result of a suspected perinatal hypoxic-ischemic event and the other presenting a typical lower motor neuron phenotype. Using exome sequencing, we identified the novel de novo variant c.752G>T; p.Arg251Leu in DYNC1H1. We thereby add this variant to the growing list of mutations in DYNC1H1 that cause SMALED1.

A retrospective analysis of memantine use in a pediatric neurology clinic.

BACKGROUND: Memantine is an N-methyl-D-aspartate receptor (NMDA-R) antagonist, approved for dementia, but also studied in pediatric autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). METHODS: We reviewed children treated with memantine in a single-centre pediatric neurology clinic. Clinical data extracted included age, sex, weight, clinical history, reason for memantine prescription, period of treatment trial and dosage, treatment response, side effects, and concomitant medications. RESULTS: Eight patients met inclusion criteria with diagnoses including developmental and epileptic encephalopathy, focal epilepsy, ASD, ADHD. Four reported clear cognitive improvement, though two of these started other concurrent treatments at the time of memantine initiation. One of three patients with poorly-controlled epilepsy, a girl with a GRIN2A variant of uncertain significance, had a clear reduction in seizure frequency. No serious adverse events were noted. CONCLUSIONS: Memantine is generally well-tolerated in children, and may have potential benefit for a broad range of pediatric neurodevelopmental disorders.

A National Spinal Muscular Atrophy Registry for Real-World Evidence.

BACKGROUND: Spinal muscular atrophy (SMA) is a devastating rare disease that affects individuals regardless of ethnicity, gender, and age. The first-approved disease-modifying therapy for SMA, nusinursen, was approved by Health Canada, as well as by American and European regulatory agencies following positive clinical trial outcomes. The trials were conducted in a narrow pediatric population defined by age, severity, and genotype. Broad approval of therapy necessitates close follow-up of potential rare adverse events and effectiveness in the larger real-world population. METHODS: The Canadian Neuromuscular Disease Registry (CNDR) undertook an iterative multi-stakeholder process to expand the existing SMA dataset to capture items relevant to patient outcomes in a post-marketing environment. The CNDR SMA expanded registry is a longitudinal, prospective, observational study of patients with SMA in Canada designed to evaluate the safety and effectiveness of novel therapies and provide practical information unattainable in trials. RESULTS: The consensus expanded dataset includes items that address therapy effectiveness and safety and is collected in a multicenter, prospective, observational study, including SMA patients regardless of therapeutic status. The expanded dataset is aligned with global datasets to facilitate collaboration. Additionally, consensus dataset development aimed to standardize appropriate outcome measures across the network and broader Canadian community. Prospective outcome studies, data use, and analyses are independent of the funding partner. CONCLUSION: Prospective outcome data collected will provide results on safety and effectiveness in a post-therapy approval era. These data are essential to inform improvements in care and access to therapy for all SMA patients.

Selective Dorsal Root Rhizotomy for Spastic Cerebral Palsy: A Longitudinal Case-Control Analysis of Functional Outcome.

BACKGROUND: The benefit of selective dorsal rhizotomies (SDR) on motor function relative to the cerebral palsy (CP) natural history remains unknown. OBJECTIVE: To determine the functional benefit of SDR over the longitudinal CP natural history. METHODS: Retrospective, single-center, case-control study of patients post-SDR after 1990. Inclusion criteria were the following: diagnosis of spastic CP, at least 1 preoperative and 1 postoperative Gross Motor Function Measure (GMFM-88), at least 1 yr of postoperative follow-up. GMFM-88 assessments were performed at 1, 2, 3, 5, 10, and 15 yr postoperatively and converted to GMFM-66. Cases were stratified by preoperative Gross Motor Function Classification System (GMFCS) and matched against their expected natural history using published reference centiles. After age 12, our cohort and matched controls were also fitted to published nonlinear mixed models of GMFM-66 evolution over time. RESULTS: Analysis included 190 patients. Median follow-up, 5.3 yr (range: 1-16.9), median age at surgery, 4.6 yr, and 81.6% of patients grouped as GMFCS II or III pre-op. SDR patients performed statistically significantly better than their expected natural history (P < .0005). At 21 yr old, a modeled benefit of 8.435 was observed for GMFCS I (P = .0051), 0.05 for GMFCS II (P = .9647), 6.31 for GMFCS III (P < .0001), and 1.191 for GMFCS IV patients (P = .0207). CONCLUSION: These results support the use of SDR in carefully selected spastic CP children.

Perceived Value of a Knowledge Translation Intervention Designed to Facilitate Burn Survivors' Work Reintegration.

Returning to work can be challenging for burn survivors. Approximately 28% never return to any form of employment, resulting in lower health-related quality of life. Open communication has been identified as a facilitator for return to work (RTW). To ease the RTW process and promote communication with coworkers and employers a knowledge translation (KT) intervention was developed for burn survivors. Following its implementation, the impact on the RTW process was evaluated. This study was a cross-sectional, mixed methods study where burn survivors included in the KT intervention were compared with a control group. Control group participants were selectively invited so that the two groups' mean age, sex, and percent total body surface area burned were similar. Semistructured interviews gathered information about their RTW process and outcomes. Qualitative data were analyzed through thematic analysis and quantitative data were summarized and compared using Mann-Whitney tests. Overall, both groups were satisfied with their RTW process. Participants from the control group identified more barriers related to support received, particularly at work, and reported more psychological symptoms such as posttraumatic stress disorder, self-consciousness, and discomfort with questions. Many participants from the KT group indicated the KT intervention gave them tools and information to provide others with a better understanding of their lived experience. It is possible that the KT intervention facilitated more open communication by empowering burn survivors to explain their situation on their own, thus reducing the prevalence of social and psychological barriers by allowing them to self-advocate for more support.

Randomized controlled trial of the immediate and long-term effect of massage on adult postburn scar.

BACKGROUND: One objective of massage therapy applied to hypertrophic scar (HSc), is to improve the structural properties so skin possesses the strength and elasticity required for normal mobility. However, research supporting this effect is lacking. The objective of this study was to characterize the changes in scar elasticity, erythema, melanin, and thickness immediately after a massage therapy session and after a 12-week course of treatment compared to intra-individual matched control scars. METHODS: We conducted a prospective, randomized, single-blinded, pragmatic, controlled, clinical trial evaluating the impact of a 12-week course of massage therapy. Seventy burn survivors consented to participate and 60 completed the study. Two homogeneous, intra-individual scars were randomized to usual care control or massage therapy plus usual care. Massage, occupational or physical therapists provided massage treatment 3x/week for 12 weeks. Scar site characteristics were evaluated weekly immediately before and after massage treatment including elasticity (Cutometer), erythema and melanin (Mexameter), and thickness (high-frequency ultrasound). Analysis of covariance (ANCOVAs) were performed to test for immediate and long-term treatment effects. A mixed-model approach was used to account for the intra-individual scars. RESULTS: Scar evaluation immediately before and after massage therapy at each time point revealed changes for all scar characteristics, but the group differences were predominantly present during the early weeks of treatment. The within group long-term analysis revealed a significant increase in elasticity, and a reduction in thickness, during the 12-week treatment period for both the control scar (CS) and massage scar (MS). The increase in elasticity reached significance at week 8 for the MS and week 10 for the CS and the reduction in thickness at week 5 for the CS and week 7 for the MS. There was no significant within group long-term differences for either erythema or melanin. There were group differences in erythema at week 8 and 11 where the CS was less erythematous than the MS. CONCLUSIONS: The immediate impact of forces applied during massage therapy may lead patients and therapists to believe that there are long-term changes in elasticity, erythema, and pigmentation, however, once baseline measures, the control scar, and time were incorporated in the analysis there was no evidence of long-term benefit. Massage therapy applied with the objective of increasing scar elasticity or reducing erythema or thickness over the long-term should be reconsidered.

Acute and Chronic Management in an Atypical Case of Ethylmalonic Encephalopathy.

Ethylmalonic encephalopathy (EE) is caused by mutations in the ETHE1 gene. ETHE1 is vital for the catabolism of hydrogen sulfide (H2S). Patients with pathogenic mutations in ETHE1 have markedly increased thiosulfate, which is a reliable index of H2S levels. Accumulation of H2S is thought to cause the characteristic metabolic derangement found in EE. Recently introduced treatment strategies in EE, such as combined use of metronidazole (MNZ) and N-acetylcysteine (NAC), are aimed at lowering chronic H2S load. Experience with treatment strategies directed against acute episodes of metabolic decompensation (e.g., hemodialysis) is limited. Here we present an unusually mild, molecularly confirmed, case of EE in a 19-year-old male on chronic treatment with MNZ and NAC. During an acute episode of metabolic decompensation, we employed continuous renal replacement therapy (CRRT) to regain metabolic control. On continuous treatment with NAC and MNZ during the months preceding the acute event, plasma thiosulfate levels ranged from 1.6 to 4 µg/mL (reference range up to 2 µg/mL) and had a mean value of 2.5 µg/mL. During the acute decompensation, thiosulfate levels were 6.7 µg/mL, with hyperlactatemia and perturbed organic acid, acylglycine, and acylcarnitine profiles. CRRT decreased thiosulfate within 24 h to 1.4 µg/mL. Following discontinuation of CRRT, mean thiosulfate levels were 3.2 µg/mL (range, 2.4-3.7 µg/mL) accompanied by clinical improvement with metabolic stabilization of blood gas, acylcarnitine, organic acid, and acylglycine profiles. In conclusion, CRRT may help to regain metabolic control in patients with EE who have an acute metabolic decompensation on chronic treatment with NAC and MNZ.

Hyperphosphatasia with mental retardation syndrome, expanded phenotype of PIGL related disorders.

Hypomorphic mutations in six different genes involved in the glycosylphosphatidylinositol (GPI) biogenesis pathway are linked to Mabry syndrome (hyperphosphatasia with mental retardation syndrome, HPMRS). This report on the third affected family with a HPMRS phenotype caused by mutations in PIGL, confirming the seventh GPI biogenesis gene linked to HPMRS. Two siblings presented with the main features of HPMRS; developmental delay, cognitive impairment, seizure disorder, skeletal deformities, and high alkaline phosphatase. We identified two heterozygous mutations in the PIGL gene (P.Trp20Ter and p.Arg88Cys). PIGL mutations have been linked to another distinctive neuroectodermal disorder: CHIME syndrome. The clinical picture of our patients expands the spectrum of PIGL-related phenotypes.

Health-Related Quality of Life for Patients With Genetically Determined Leukoencephalopathy.

BACKGROUND: We attempted to characterize the health-related quality of life in patients with genetically determined leukoencephalopathies as it relates to the severity of clinical features and the presence or absence of a precise molecular diagnosis. METHODS: Health-related quality of life was assessed using the Pediatric Quality of Life Inventory model (Pediatric Quality of Life Inventory 4.0 Self- and Proxy-reports) on 59 patients diagnosed with genetically determined leukoencephalopathies. In total, 38 male and 21 female patients ranging from one to 32 years of age (mean nine years), as well as their parents, completed the Pediatric Quality of Life Inventory health-related quality of life measures. In addition, participants completed detailed standardized clinical assessments or questionnaires. The correlation between health-related quality of life results and the severity of the clinical features, as well as the presence or absence of a molecular diagnosis, were analyzed. RESULTS: Patients with more severe clinical features showed statistically significant lower total Pediatric Quality of Life Inventory scores. More specifically, lower health-related quality of life was noted in children with sialorrhea, gastrostomy, and dystonia and in children who use a wheelchair. CONCLUSIONS: Patients with more severe clinical features experience a lower quality of life. Our study further highlights the importance of addressing both physical and psychosocial issues and discussing perception of quality of life with both parents and children. A larger multicenter prospective study will be needed to further define the burden of these diseases and to identify modifiable factors.

A novel homozygous AP4B1 mutation in two brothers with AP-4 deficiency syndrome and ocular anomalies.

Adaptor protein complex-4 (AP-4) is a heterotetrameric protein complex which plays a key role in vesicle trafficking in neurons. Mutations in genes affecting different subunits of AP-4, including AP4B1, AP4E1, AP4S1, and AP4M1, have been recently associated with an autosomal recessive phenotype, consisting of spastic tetraplegia, and intellectual disability (ID). The overlapping clinical picture among individuals carrying mutations in any of these genes has prompted the terms "AP-4 deficiency syndrome" for this clinically recognizable phenotype. Using whole-exome sequencing, we identified a novel homozygous mutation (c.991C>T, p.Q331*, NM_006594.4) in AP4B1 in two siblings from a consanguineous Pakistani couple, who presented with severe ID, progressive spastic tetraplegia, epilepsy, and microcephaly. Sanger sequencing confirmed the mutation was homozygous in the siblings and heterozygous in the parents. Similar to previously reported individuals with AP4B1 mutations, brain MRI revealed ventriculomegaly and white matter loss. Interestingly, in addition to the typical facial gestalt reported in other AP-4 deficiency cases, the older brother presented with congenital left Horner syndrome, bilateral optic nerve atrophy and cataract, which have not been previously reported in this condition. In summary, we report a novel AP4B1 homozygous mutation in two siblings and review the phenotype of AP-4 deficiency, speculating on a possible role of AP-4 complex in eye development.