Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders.

BACKGROUND: Variants in HECW2 have recently been reported to cause a neurodevelopmental disorder with hypotonia, seizures and impaired language; however, only six variants have been reported and the clinical characteristics have only broadly been defined. METHODS: Molecular and clinical data were collected from clinical and research cohorts. Massive parallel sequencing was performed and identified individuals with a HECW2-related neurodevelopmental disorder. RESULTS: We identified 13 novel missense variants in HECW2 in 22 unpublished cases, of which 18 were confirmed to have a de novo variant. In addition, we reviewed the genotypes and phenotypes of previously reported and new cases with HECW2 variants (n=35 cases). All variants identified are missense, and the majority of likely pathogenic and pathogenic variants are located in or near the C-terminal HECT domain (88.2%). We identified several clustered variants and four recurrent variants (p.(Arg1191Gln);p.(Asn1199Lys);p.(Phe1327Ser);p.(Arg1330Trp)). Two variants, (p.(Arg1191Gln);p.(Arg1330Trp)), accounted for 22.9% and 20% of cases, respectively. Clinical characterisation suggests complete penetrance for hypotonia with or without spasticity (100%), developmental delay/intellectual disability (100%) and developmental language disorder (100%). Other common features are behavioural problems (88.9%), vision problems (83.9%), motor coordination/movement (75%) and gastrointestinal issues (70%). Seizures were present in 61.3% of individuals. Genotype-phenotype analysis shows that HECT domain variants are more frequently associated with cortical visual impairment and gastrointestinal issues. Seizures were only observed in individuals with variants in or near the HECT domain. CONCLUSION: We provide a comprehensive review and expansion of the genotypic and phenotypic spectrum of HECW2 disorders, aiding future molecular and clinical diagnosis and management.

Predominant and novel de novo variants in 29 individuals with ALG13 deficiency: Clinical description, biomarker status, biochemical analysis, and treatment suggestions.

Asparagine-linked glycosylation 13 homolog (ALG13) encodes a nonredundant, highly conserved, X-linked uridine diphosphate (UDP)-N-acetylglucosaminyltransferase required for the synthesis of lipid linked oligosaccharide precursor and proper N-linked glycosylation. De novo variants in ALG13 underlie a form of early infantile epileptic encephalopathy known as EIEE36, but given its essential role in glycosylation, it is also considered a congenital disorder of glycosylation (CDG), ALG13-CDG. Twenty-four previously reported ALG13-CDG cases had de novo variants, but surprisingly, unlike most forms of CDG, ALG13-CDG did not show the anticipated glycosylation defects, typically detected by altered transferrin glycosylation. Structural homology modeling of two recurrent de novo variants, p.A81T and p.N107S, suggests both are likely to impact the function of ALG13. Using a corresponding ALG13-deficient yeast strain, we show that expressing yeast ALG13 with either of the highly conserved hotspot variants rescues the observed growth defect, but not its glycosylation abnormality. We present molecular and clinical data on 29 previously unreported individuals with de novo variants in ALG13. This more than doubles the number of known cases. A key finding is that a vast majority of the individuals presents with West syndrome, a feature shared with other CDG types. Among these, the initial epileptic spasms best responded to adrenocorticotropic hormone or prednisolone, while clobazam and felbamate showed promise for continued epilepsy treatment. A ketogenic diet seems to play an important role in the treatment of these individuals.

A Mercury Toxicity Case Complicated by Hyponatremia and Abnormal Endocrinological Test Results.

Mercury (Hg) poisoning is considered a rare disease by the National Institutes of Health and the diagnosis can present great challenges to clinicians. Children who are exposed to Hg can present with a wide variety of symptoms, including acrodynia, tremor, excessive salivation, and psychiatric symptoms, including insomnia. However, endocrinologic manifestations from Hg exposure are less well known. This is a case report of a 12-year-old boy who presented with body rash, irritability, insomnia, and profuse sweating after returning from a summer camp. The child was initially managed in the outpatient setting, and the investigation was mainly targeted toward infectious etiology, including Rocky Mountain spotted fever and Lyme disease. He was eventually admitted to the hospital with altered mental status and was noted to have hyponatremia with serum sodium of 121 mEq/L. Thyroid studies also revealed elevated free thyroxine levels in the presence of normal triiodothyronine and thyrotropin. The patient developed hypertension and tachycardia, and was found to have elevated 24-hour vanillylmandelic acid and metanephrines. Finally, heavy metal measurements revealed a blood Hg level that was greater than the reference values of 0 to 9 ng/mL. Chelation treatment with 2,3-dimercaptopropane-1-sulfonate was subsequently initiated and over a period of 8 months his symptoms resolved and his thyroid function test returned to normal. This case highlights some of the challenges commonly encountered in identifying Hg exposure. More importantly, it illustrates that exposure to Hg should be considered in children who present with the symptoms and abnormal endocrinologic test results described in this report.

Cerebellar mutism and reversible cytotoxic edema in influenza B-associated encephalopathy.

BACKGROUND: Influenza virus-associated neurological complications are rare, though well-documented, especially in children. Encephalopathy and seizures are the most common complications and are typically associated with influenza A infection. Cerebellar mutism has been rarely reported in association with influenza B infection. PATIENT: We describe a 3-year-old boy who presented with cough, fever, altered mental status, seizure, hypotonia, and mutism. He tested positive for influenza B virus. His brain magnetic resonance imaging showed reversible cytotoxic edema limited to the middle cerebellar peduncles and the dentate nuclei. Other viral, vascular, toxic, and metabolic causes were ruled out. CONCLUSION: Our patient represents a case of cerebellar mutism associated with influenza B encephalopathy in which the brain magnetic resonance imaging scan showed reversible cytotoxic edema limited to the middle cerebellar peduncles and the dentate nuclei. This clinicoradiological correlation supports other reports in which the dentate nuclei play a major rule in the pathogenesis of cerebellar mutism.

Aripiprazole-induced seizure in a 3-year-old child: a case report and literature review.

Aripiprazole is an atypical antipsychotic medication that is a partial dopamine D(2) and serotonin 5-hydroxytryptamine (1A) receptor agonist and 5-hydroxytryptamine (2A) receptor antagonist. It has a safer profile compared to other antipsychotic medications with regard to its effect on weight, glucose tolerance, prolactin level, and cardiac conduction. The common neurological adverse effects include headache, agitation, insomnia, sleepiness, and extrapyramidal symptoms. Seizures have not been reported in the pediatric population and only twice in adult patients. Here, we report a case of a healthy 3-year-old child who experienced prolonged lethargy, dystonia, and 2 witnessed seizures after incidental ingestion of 30 mg of aripiprazole. To our knowledge, this is the first reported case of aripiprazole-induced seizures in a child.

Unusual case of West Nile Virus flaccid paralysis in a 10-year-old child.

West Nile virus infection is asymptomatic in most cases. West Nile virus neuroinvasive disease includes encephalitis, meningitis, and/or acute flaccid paralysis. In children, acute flaccid paralysis as the solo presentation of West Nile virus disease is rare. It develops abruptly and progresses rapidly early in the disease course. We report on a 10-year-old child who presented with a slowly progressive left leg flaccid paralysis over 4 weeks. He tested positive for West Nile virus in both blood and cerebrospinal fluid. Spinal MRI showed enhancement of the ventral nerve roots. This was also supported by electrophysiological studies. One week after the plateauing of his left leg paralysis, he was readmitted to the hospital with left hand weakness. Complete recovery of his recurrent weakness was observed after prompt 5-day course of intravenous immunoglobulin G therapy. However, no improvement was noticed in the left foot drop. To our knowledge, this is the first case report of West Nile virus disease in children presented with a slowly progressive flaccid paralysis, and a recurrent weakness recovered after intravenous immunoglobulin G administration.

Evaluation of the child with acute ataxia: a systematic review.

Evaluation of acute ataxia in a child poses a dilemma for the clinician in determining the extent and timing of initial screening tests. This article reviews the evidence concerning the diagnostic yield of commonly ordered tests in evaluating the child with acute ataxia. The literature revealed the following frequencies of laboratory screening abnormalities in children with acute ataxia: CT (∼2.5%), MRI (∼5%), lumbar puncture (43%), EEG (42%), and toxicology (49%). In most studies, abnormalities detected by these screening tests were nondiagnostic. There are insufficient data to assess yields of testing for autoimmune disorders or inborn errors of metabolism. A toxicology screen should be considered in all children presenting with acute ataxia. Neuroimaging should be considered in all children with new onset ataxia. Cerebrospinal fluid analysis has limited diagnostic specificity unless clinically indicated. Studies to examine neurophysiology testing did have sufficient evidence to support their use. There is insufficient evidence to establish a role for autoantibody testing or for routine screening for inborn error of metabolism in children presenting with acute ataxia. Finally, in a child presenting with ataxia and opsoclonus myoclonus, urine catecholamine testing for occult neuroblastoma is recommended. Nuclear scan may be considered, however, there is insufficient evidence for additional body imaging.