Clinical, neuroimaging, and molecular spectrum of TECPR2-associated hereditary sensory and autonomic neuropathy with intellectual disability.

Bi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus. Through international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms. A cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea as core manifestations. A review of brain magnetic resonance imaging scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing ß-propeller repeats. Despite constituting nearly half of disease-associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1221 in the general and 1/155 in the Jewish Ashkenazi populations. Based on clinical, neuroimaging, and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.

B3GALNT2-Related Dystroglycanopathy: Expansion of the Phenotype with Novel Mutation Associated with Muscle-Eye-Brain Disease, Walker-Warburg Syndrome, Epileptic Encephalopathy-West Syndrome, and Sensorineural Hearing Loss.

Mutations in B3GALNT2, encoding a glycosyltransferase enzyme involved in α-dystroglycan glycosylation, have been recently associated with dystroglycanopathy, a well-recognized subtype of congenital muscular dystrophy (CMD). Only a few cases have been reported with B3GALNT2-related dystroglycanopathy with variable severity ranging from mild CMD to severe muscle-eye-brain disease. Here, we describe a child with a novel homozygous nonsense mutation in B3GALNT2. The affected child has severe neurological disease since birth, including muscle disease manifested as hypotonia, muscle weakness, and wasting with elevated creatine kinase, eye disease including microphthalmia and blindness, brain disease with extensive brain malformations including massive hydrocephalus, diffuse cobblestone-lissencephaly, deformed craniocervical junction, and pontocerebellar hypoplasia. The clinical and radiologic findings are compatible with a diagnosis of severe muscle-eye-brain disease and more specifically Walker-Warburg syndrome. A more distinct aspect of the clinical phenotype in this child is the presence of refractory epilepsy in the form of epileptic spasms, epileptic encephalopathy, and West syndrome, as well as sensorineural hearing loss. These findings could expand the phenotype of B3GALNT2-related dystroglycanopathy. In this report, we also provide a detailed review of previously reported cases with B3GALNT2-related dystroglycanopathy and compare them to our reported child. In addition, we study the genotype-phenotype correlation in these cases.

Diagnosis and management of infantile epileptic spasms syndrome (IESS) in Gulf Cooperation Council (GCC) countries: Expert consensus statement.

Despite the availability of international recommendations for the management of Infantile Epileptic Spasms Syndrome (IESS), there is a lack of recommendations adapted to the local context of clinical practice of pediatric neurology in the Gulf Cooperation Council (GCC) countries. By an initiative from the Saudi Pediatric Neurology Society (SPNS), a literature review was performed and an expert panel comprised of 13 pediatric neurologists from all GCC countries (Saudi Arabia, Kuwait, Bahrain, Oman, Qatar, and the United Arab Emirates) was subsequently convened to discuss all issues related to the management and diagnosis practices of IESS in the GCC. The overall aim of this consensus document was to develop practical recommendations to support the care of patients with IESS in the GCC and to reflect on how clinical management approaches compare with those adopted internationally.

Gene Therapy for Duchenne Muscular Dystrophy: Unlocking the Opportunities in Countries in the Middle East and Beyond.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder which leads to progressive muscle degeneration and weakness. Most patients die from cardiac or respiratory failure. Gene transfer therapy offers a promising approach to treating this disorder. OBJECTIVE: Given the genetic disease burden, family size, and the high consanguinity rates in the Middle East, our objective is to address current practices and challenges of DMD patient care within two countries in this region, namely the United Arab Emirates and Kuwait, and to outline readiness for gene therapy. METHODS: An expert panel meeting was held to discuss the DMD patient journey, disease awareness, current management of DMD, challenges faced and recommendations for improvement. Opportunities and challenges for gene therapy in both countries were also deliberated. A pre-meeting survey was conducted, and the results were used to guide the discussion during the meeting. RESULTS: DMD awareness is poor resulting in a delay in referral and diagnosis of patients. Awareness and education initiatives, along with an interconnected referral system could improve early diagnosis. Genetic testing is available in both countries although coverage varies. Corticosteroid therapy is the standard of care however there is often a delay in treatment initiation. Patients with DMD should be diagnosed and managed by a multi-disciplinary team in centers of excellence for neuromuscular disorders. Key success factors to support the introduction of gene therapy include education and training, timely and accessible genetic testing and resolution of reimbursement and cost issues. CONCLUSION: There are many challenges facing the management of DMD patients in the United Arab Emirates and Kuwait and most likely other countries within the Middle East. Successful introduction of gene therapy to treat DMD will require careful planning, education, capacity building and prioritization of core initiatives.

RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum.

OBJECTIVE: Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1-related disease, and to identify possible genotype-phenotype relationships. METHODS: We performed a multinational cross-sectional survey among 20 patients with biallelic RARS1 variants identified by next-generation sequencing techniques. Clinical data, brain MRI findings and genetic results were analyzed. Additionally, ArgRS activity was measured in fibroblasts of four patients, and translation of long and short ArgRS isoforms was quantified by western blot. RESULTS: Clinical presentation ranged from severe (onset in the first 3 months, usually with refractory epilepsy and early brain atrophy), to intermediate (onset in the first year with nystagmus and spasticity), and mild (onset around or after 12 months with minimal cognitive impairment and preserved independent walking). The most frequent RARS1 variant, c.5A>G, led to mild or intermediate phenotypes, whereas truncating variants and variants affecting amino acids close to the ArgRS active centre led to severe phenotypes. ArgRS activity was significantly reduced in three patients with intermediate and severe phenotypes; in a fourth patient with intermediate to severe presentation, we measured normal ArgRS activity, but found translation mainly of the short instead of the long ArgRS isoform. INTERPRETATION: Variants in RARS1 impair ArgRS activity and do not only lead to a classic hypomyelination presentation with nystagmus and spasticity, but to a wide spectrum, ranging from severe, early-onset epileptic encephalopathy with brain atrophy to mild disease with relatively preserved myelination.

Effect of reducing the recording time of standard EEGs on the detection of EEG-abnormalities in the management of the epilepsies of childhood.

PURPOSE: The ILAE recommends baseline recordings of 30 min to detect abnormalities supporting a clinical diagnosis of epilepsy in children. A shorter recording time may be better tolerated by children and be more resource-efficient. Our aim was to determine how many abnormalities supporting a diagnosis of epilepsy would be missed by reducing the recording time of paediatric standard electroencephalograms (EEGs) from 20 to 15 min. METHODS: We evaluated standard EEGs of 300 patients aged 2 months to 17 years referred consecutively with confirmed or suspected epilepsy. EEGs were recorded for 20 min on digital media. A digital copy of each EEG was truncated to give consecutive sequences of 10 min (sequence "A") and 5 min duration (sequences "B" and "C" respectively). A panel of EEG raters blinded to the children's' details other than age identified these sequences as "normal" or "abnormal" if they contained spike waves, discrete sharp waves or notched slow waves in the respective EEG period. RESULTS: EEGs of 297 children were analysed (three were omitted for technical reasons). 109 out of 297 EEGs (37%) had specific abnormalities supportive of a diagnosis of an epilepsy. 17 of these EEGs showed the abnormality in EEG sequences "B" or "C" and 7 (95% CI: 1.9-12.2) out of these demonstrated the abnormality in sequence "C" only. 105 out of 297 EEGs had non-specific findings. CONCLUSION: We conclude that reducing the recording time of standard EEGs to 15 min may miss abnormalities in 2.36% [95% CI: 0.63-4.09%] overall and 6.42% [95% CI: 2.2-11.8%] of those with an abnormality supportive of an epilepsy to explain the reported symptoms. This result should inform any future discussions on seeking resource-efficiencies.

Acute disseminated encephalomyelitis mimicking late CNS relapse of acute lymphoblastic leukaemia: case report.

BACKGROUND: Acute encephalomyelopathy occurring after an allogeneic bone marrow transplant for leukaemia is a diagnostic emergency. The diagnosis can be challenging since there is a wide set of alternative diagnoses, including opportunistic infections and relapse of the leukaemia. CASE PRESENTATION: A 13-year old girl presented with a severe acute myelopathy and encephalopathy. She was in prolonged remission from a central nervous system and bone marrow relapse of an acute lymphoblastic leukaemia, treated with allogeneic bone marrow transplantation. Neuroimaging showed multifocal grey and white matter lesions of demyelinating appearance in the brain and entire spine. Immunophenotyping and cytogenetic investigations of the girl's cerebrospinal fluid lymphocytosis excluded a late central nervous system relapse of her leukaemia. The diagnosis was acute disseminated encephalomyelitis. With standard immunosuppressive therapy, the girl had early cerebral recovery but a prolonged period of recovery from her myelopathy. CONCLUSION: Acute disseminated encephalomyelitis should be considered in the differential diagnosis of acute encephalomyelopathy after bone marrow transplantation for leukaemia. Demyelinating syndromes such as acute disseminated encephalomyelitis may be late sequelae of bone marrow transplantation.