Parkinsonism-dystonia-2: Case-series study from Saudi Arabia.

Parkinsonism-dystonia-2 PKDYS2 is an autosomal-recessive disorder, caused by pathogenic biallelic variants in SLC18A2 which encodes the vesicular monoamine transporter (VMAT2) protein. PKDYS2 is a treatable neurotransmitter disease, and the rate of diagnosis of this disorder has increased significantly with the advance of genomic technologies. Our report highlights a novel pathologic variant in one case and a novel finding on MRI Brain, consisting of a normal symmetrical signal intensity in the dorsal brainstem and pons, and it substantiates the significance of genetic testing in the evaluation of children with developmental delays, which influences clinical decisions to enhance patient outcomes.

Patient demographics and characteristics from an ambispective, observational study of patients with duchenne muscular dystrophy in Saudi Arabia.

Duchenne muscular dystrophy (DMD) is a rare neuromuscular disorder that is characterized by progressive muscle weakness, resulting in disability and premature death. Onset of symptoms typically occurs at 2-3 years of age, and disease progression is managed through treatment with corticosteroids. The aim of this interim analysis is to increase disease awareness and improve patient management in Saudi Arabia (SA) through the use of data from an ongoing ambispective, observational, multicenter study evaluating characteristics of patients aged 1-14 years with genetically confirmed DMD in SA. This interim analysis examined the secondary outcomes from the study-the demographics and clinical characteristics of patients included retrospectively [data recorded (enrollment visit) between January 2014 and September 2020] and prospectively between September 2020 and April 2021. The primary outcome-the list of DMD gene mutations for the study population-will be reported at a later date. There were 177 eligible patients. Mean, standard deviation (SD) age at enrollment was 7.5 (3.0) years. Median (min, max) age at diagnosis was 7.0 (1.3, 13.8) years. At enrollment, 28.9% of patients were full-time wheelchair users, 50.0% of ambulatory patients could run, and 63.9% could climb stairs. The mean (SD) ages of patients at enrollment who were unable to run and climb stairs were 8.0 (2.7) and 7.6 (3.0) years, respectively. Speech delay (19.4%) and learning difficulties (14.9%) were the most commonly reported intellectual impairments. Physical therapy (84.2%) was the most common choice for initial management of DMD. Only 40.7% of patients received corticosteroid therapy as part of their initial management plan, rising to 59.1% at enrollment. Devices were given to 28.8% of patients for initial management, most commonly ankle-foot orthoses (26.0%) and wheelchairs (6.2%). This analysis reports data from the largest study to date to capture demographics and clinical characteristics of DMD patients in SA. The interim results show a relatively late DMD diagnosis age compared with that in other countries, and a need for improved adherence to international DMD standard of care guidelines. Therefore, there is an urgent requirement for improved DMD education and awareness among healthcare professionals and the public in SA.

Epilepsy in patients with WWOX-related epileptic encephalopathy (WOREE) syndrome

Objective: Epileptic encephalopathy (EE) is difficult to diagnose and manage. It can be caused by a variety of disorders, and its aetiology may guide management and prognosis. The human gene for WW domain-containing oxidoreductase (WWOX) has been associated with epileptic encephalopathy, which presents in infancy with seizures, psychomotor delay, microcephaly, and optic atrophy. Methods: We report nine patients with WWOX-related EE from six families. We provide detailed descriptions of clinical presentations, imaging findings, neurophysiological manifestations, and related mutations. Whole-exome sequencing (WES) was used to identify the mutations in the WWOX gene. Results: We established correlations between genotype and phenotype in our cases and previously reported cases. Significance: Our data support previously reported findings regarding WWOX-related EE, indicating the importance of the human WWOX gene in brain development and the association between WWOX mutations and EE. Our study also highlights the power of WES, particularly in clinically challenging cases.

Successful treatment of epilepsia partialis continua with perampanel: two pediatric cases.

Epilepsia partialis continua (EPC) is a form of focal motor status epilepticus, associated with multiple etiologies. Etiology-specific treatments, such as hemispherotomy for Rasmussen encephalitis, lesionectomy for focal cortical dysplasia, and metabolic correction for non-ketotic hyperglycemia, have proven to be efficacious in treating EPC, but, in general, EPC is difficult to treat and often drug-resistant, and there is little evidence to guide therapy. We report the successful treatment of EPC with perampanel in two pediatric patients. The first patient was a 12-year-old boy with neuronal ceroid lipofuscinosis (NCL) who started to have EPC around the age of 10 years, characterized by left hemifacial myoclonic twitches and hemi-body jerks that were almost continuous throughout the day and disappeared during sleep. He had failed several antiepileptic drugs (AEDs). The EPC stopped within three days of initiating perampanel. The second patient was a six-year-old boy with POLG-related mitochondrial disease who presented to the emergency room with continuous jerky movements of the right arm and face after a trivial head injury. After failing several AEDs, including a midazolam drip, the EPC was controlled with perampanel. Both patients showed dramatic improvement and continue to show sustained efficacy after around five months of follow-up. Based on our observations, perampanel, which has a unique mechanism of action, appears to be a promising therapeutic option for treating EPC. [Published with video sequence].

Selenoprotein N-related myopathy: a retrospective natural history study to guide clinical trials.

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.

Gender and Hemispheric Differences in Epilepsy Diagnosed by Voxel-based Morphometry (VBM) Method: a Pilot Cortical Thickness Study.

INTRODUCTION: Voxel-based morphometry (VBM) is a neuroimaging analysis technique that allows investigation of focal differences in brain anatomy, using the statistical approach of statistical parametric mapping. Gender changes are probably expressed in the human brain in the form of functional and anatomical organization. AIM: Our aim was to study gender differences and anatomical abnormalities in epilepsy patients (EP) by voxel-based morphometry (VBM) methods. METHODS: Cortical thickness analysis of whole brain was performed in 28 patients with EP and 30 controls for gender and hemispheric differences. RESULTS: Cortical thickness abnormalities were more widespread in left side of the brain in EP; while in female changes were mostly seen in temporal areas, frontal regions were more affected in male. CONCLUSION: Our study confirmed that gender and laterality are important factors determining the brain damage in EP.

MYL2-associated congenital fiber-type disproportion and cardiomyopathy with variants in additional neuromuscular disease genes; the dilemma of panel testing.

Next-generation sequencing has led to transformative advances in our ability to diagnose rare diseases by simultaneously sequencing dozens, hundreds, or even entire genomes worth of genes to efficiently identify pathogenic mutations. These studies amount to multiple hypothesis testing on a massive scale and not infrequently lead to discovery of multiple genetic variants whose relative contributions to a patient's disease are unclear. Panel testing, in particular, can be problematic because each of the many genes being sequenced might represent a plausible explanation for a given case. We performed targeted gene panel analysis of 43 established neuromuscular disease genes in a patient with congenital fiber-type disproportion (CFTD) and fatal infantile cardiomyopathy. Initial review of variants identified changes in four genes that could be considered relevant candidates to cause this child's disease. Further analysis revealed that two of these are likely benign, but a homozygous frameshift variant in the myosin light chain 2 gene, MYL2, and a heterozygous nonsense mutation in the nebulin gene, NEB, met criteria to be classified as likely pathogenic or pathogenic. Recessive MYL2 mutations are a rare cause of CFTD associated with both skeletal and cardiomyopathy, whereas recessive NEB mutations cause nemaline myopathy. Although the proband's phenotype is likely largely explained by the MYL2 variant, the heterozygous pathogenic NEB variant cannot be ruled out as a contributing factor. This case illustrates the complexity when analyzing large numbers of variants from targeted gene panels in which each of the genes might plausibly contribute to the patient's clinical presentation.

Spectrum of Neuromuscular Disorders With HyperCKemia From a Tertiary Care Pediatric Neuromuscular Center.

Elevated creatine kinase is a useful screening test in the diagnostic workup of patients with neuromuscular disorders. We did a retrospective study of children with hyperCKemia (>175 IU/L) who were followed in the neuromuscular program of a tertiary care pediatric center from 2005 to 2016. Patients with hyperCKemia were divided into 2 groups: myopathic and nonmyopathic. Within the myopathic group, there were 3 arbitrary subgroups based on creatine kinase values: A (creatine kinase >10 times normal), B (creatine kinase 5-10 times normal), and C (creatine kinase 1-5 times normal). The 3 major categories of myopathies across all the subgroups were muscular dystrophies (commonest) followed by metabolic myopathies and inflammatory myopathies. Among the nonmyopathic causes of hyperCKemia, spinal muscular atrophy was the commonest. Muscular dystrophies should be considered in children with hyperCKemia, muscle weakness, or calf hypertrophy, and metabolic myopathies to be considered in children with recurrent rhabdomyolysis.

Neuralgic amyotrophy in children.

INTRODUCTION: Neuralgic amyotrophy (NA) is characterized by the clinical triad of pain, muscle weakness/atrophy, and sensory symptoms. METHODS: We retrospectively identified children (≤18 years old) over the course of 15 years (2003-2017) at a single pediatric center. RESULTS: We included 22 patients (8 females and 14 males, 6-18 years old); pain was the presenting manifestation in all of them. Clinical weakness involving the periscapular muscles was observed in 16 patients and scapular winging in 13 patients. Two patients had preceding viral infection. Electromyography was performed in 21 patients: sensory nerve abnormalities were detected in 5, and neurogenic changes were most commonly observed in the serratus anterior muscle. Treatment was mainly supportive, although 4 patients received immunotherapy. Persistent pain and residual motor deficits were observed in more than half of the patients at follow-up. DISCUSSION: NA is rare in children but clinicians should be aware of this entity to avoid delays in diagnosis. In our series, presentation was similar to that seen in adults. Muscle Nerve 57: 932-936, 2018.

Brain involvement in Charcot-Marie-Tooth disease due to ganglioside-induced differentiation associated-protein 1 mutation.

Charcot-Marie-Tooth (CMT) due to ganglioside-induced differentiation associated-protein 1 (GDAP1) gene mutation can be inherited as an autosomal recessive (severe phenotype) or dominant (milder phenotype) disorder. GDAP1 protein, located in the outer mitochondrial membrane, is involved in the mitochondrial fission. Brain imaging abnormalities have not been reported in this condition. We described an 8-year-old boy who had an early onset autosomal recessive neuropathy. Whole exome sequencing revealed compound heterozygous mutations in the GDAP1 gene: c.313_313delA, p.Arg105Glufs*3 - a novel mutation (maternally inherited) and c.358C>T, pR120W - a known pathogenic mutation (paternally inherited). He had abnormal brain MRI findings since infancy localized to the middle cerebellar peduncles and cerebellar white matter with sparing of the supratentorial brain. We speculate that GDAP1 protein due to its widespread distribution and mitochondrial location is responsible for these imaging abnormalities. This report expands the spectrum of brain imaging abnormalities seen in different types of CMT.

Spectrum of Nondystrophic Skeletal Muscle Channelopathies in Children.

BACKGROUND: The nondystrophic skeletal muscle channelopathies are a group of disorders caused by mutations of various voltage-gated ion channel genes, including nondystrophic myotonia and periodic paralysis. METHODS: We identified patients with a diagnosis of muscle channelopathy from our neuromuscular database in a tertiary care pediatric center from 2005 to 2015. We then performed a retrospective review of their medical records for demographic characteristics, clinical features, investigations, treatment, and follow-up. RESULTS: Thirty-three patients were identified. Seventeen had nondystrophic myotonia. Seven of them had chloride channelopathy (four Becker disease and three Thomsen disease). Warm-up phenomenon and muscle hypertrophy were common clinical manifestations in this subgroup. Ten patients had sodium channelopathy (four paramyotonia congenita and six other sodium channel myotonia). Stiffness of the facial muscles was an important presenting symptom, and eyelid myotonia was a common clinical finding in this subgroup. The majority of these patients had electrical myotonia. Mexiletine was effective in controlling the symptoms in patients who had received treatment. Sixteen children had periodic paralysis (four hyperkalemic periodic paralysis, eight hypokalemic periodic paralysis, and four Andersen-Tawil syndrome). Acetazolamide was commonly used to prevent paralytic attacks and was found to be effective. CONCLUSIONS: Nondystrophic muscle channelopathies present with diverse clinical manifestations (myotonia, muscle hypertrophy, proximal weakness, swallowing difficulties, and periodic paralysis). Cardiac arrhythmias are potentially life threatening in Andersen-Tawil syndrome. Timely identification of these disorders is helpful for effective symptomatic management and genetic counseling.

Limbic encephalitis in a child: an atypical presentation.

BACKGROUND: Limbic encephalitis is a rare disorder with a generally subacute onset evolving over days to weeks. Patients present with a variable combination of memory loss, seizures, and psychiatric disturbance, and it is not rare for patients to be initially misdiagnosed. PATIENT: We describe a previously healthy 12-year-old boy who developed his first seizures at 8 years of age. He had a total of eight prolonged focal seizures, each followed by a month of behavioral changes and short-term memory loss. There was no family history of seizures or other neurological disorders, and he had an otherwise unremarkable neonatal and medical history. RESULTS: Magnetic resonance imaging during each episode of seizures showed alternating unilateral brain hemispheric involvement consistent with limbic encephalitis that was followed by resolution for a total of six times. Despite a negative laboratory evaluation for a large panel of paraneoplastic antibodies, the clinical scenario and exclusion of other possible disorders made recurrent limbic encephalitis the most likely diagnosis. CONCLUSION: Limbic encephalitis is a rare disorder that is diagnosed primarily on the basis of clinical criteria and is often associated with the presence of a paraneoplastic antibody. However, lack of a positive paraneoplastic antibody in a patient with a triad of seizure, behavioral changes, and short-term memory loss does not exclude the diagnosis. The unique presentation in a seronegative patient may indicate an unrecognized antibody.