Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia.

PURPOSE: Neurodevelopmental disorders (NDDs) encompass a spectrum of genetically heterogeneous disorders with features that commonly include developmental delay, intellectual disability, and autism spectrum disorders. We sought to delineate the molecular and phenotypic spectrum of a novel neurodevelopmental disorder caused by variants in the GNAI1 gene. METHODS: Through large cohort trio-based exome sequencing and international data-sharing, we identified 24 unrelated individuals with NDD phenotypes and a variant in GNAI1, which encodes the inhibitory Gαi1 subunit of heterotrimeric G-proteins. We collected detailed genotype and phenotype information for each affected individual. RESULTS: We identified 16 unique variants in GNAI1 in 24 affected individuals; 23 occurred de novo and 1 was inherited from a mosaic parent. Most affected individuals have a severe neurodevelopmental disorder. Core features include global developmental delay, intellectual disability, hypotonia, and epilepsy. CONCLUSION: This collaboration establishes GNAI1 variants as a cause of NDDs. GNAI1-related NDD is most often characterized by severe to profound delays, hypotonia, epilepsy that ranges from self-limiting to intractable, behavior problems, and variable mild dysmorphic features.

Biallelic variants in the transcription factor PAX7 are a new genetic cause of myopathy.

PURPOSE: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established. METHODS: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease. RESULTS: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration. CONCLUSION: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.

Acute psychosis in children: do not miss immune-mediated causes.

New-onset psychosis in children represents a complex presenting symptom. Psychosis can be attributable to a combination of factors and etiologies, and all possible causes must be systematically examined. There is growing evidence that a proportion of psychosis/ psychiatric manifestations in children may be immunemediated, and physicians should consider this etiology in each presentation of first-episode psychosis. Immunemediated encephalopathies/encephalitis are increasingly being recognized in children with antibodies to N-methyl-D-aspartate receptor, Leucine-rich gliomainactivated 1 or other central nervous system antigens such as Contactin-associated protein-like 2, glutamic acid decarboxylase, alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid or Gamma-aminobutyric acid B. In this study, we describe 3 cases of immune-mediated encephalopathy/encephalitis with prominent psychiatric symptoms at presentation, and suggest a practical diagnostic and treatment approach for children with acute psychosis of an immune-mediated cause.

Hereditary Hyperekplexia in Saudi Arabia.

BACKGROUND: Hyperekplexia is a rare disorder characterized by exaggerated startle responses to unexpected sensory stimuli, recurrent apneas, and stiffness. Only few studies have been published on this disorder in populations with high rates of consanguinity. METHODS: We retrospectively reviewed Saudi patients with genetically confirmed hereditary hyperekplexia using a standard questionnaire that was sent to nine major referral hospitals in Saudi Arabia. RESULTS: A total of 22 Saudi patients (11 males, 11 females) from 20 unrelated families who had hereditary hyperekplexia were included. Based on molecular studies, they were classified into different subtypes: SLC6A5 variant (12 patients, 54.5%), GLRB variant (seven patients, 31.8%), and GLRA1 variant (three patients, 13.7%). All patients were homozygous for the respective causal variant. The combined carrier frequency of hereditary hyperekplexia for the encountered founder mutations in the Saudi population is 10.9 per 10,000, which translates to a minimum disease burden of 13 patients per 1,000,000. CONCLUSION: Our study provides comprehensive epidemiologic information, prevalence figures, and clinical characteristics of a large cohort of patients with hereditary hyperekplexia.

Extending the use of stiripentol to SLC13A5-related epileptic encephalopathy.

INTRODUCTION: SLC13A5-related epileptic encephalopathy is a recently described autosomal recessive disorder that is characterized by infantile epilepsy and developmental delay. Seizures are markedly drug resistant and often induced by fever; they mainly occur in clusters, sometimes evolving into status epilepticus. METHODS AND RESULTS: We report the use of stiripentol as an adjunctive therapy in three siblings with drug-resistant SLC13A5-related epilepsy. The three patients showed remarkable improvement in the severity and frequency of seizures, status epilepticus, emergency department visits, and alertness. CONCLUSION: These observations extend the use of stiripentol beyond the classical Dravet syndrome, and further studies on the use of this drug in drug-resistant epilepsy, mainly of genetic origin, are warranted.