ABSTRACT
The calcium/calmodulin-dependent protein kinase II-beta ( CAMK2B ) gene is important for calcium signaling and glutamatergic synapses, which impacts neuroplasticity and learning. Mutations in the CAMK2B gene, which cause autosomal dominant mental retardation 54 (Online Mendelian Inheritance in Man # 617799), can have multisystemic clinical impact. Due to the rarity of CAMK2B mutations at present, case reports about patients with CAMK2B mutations are limited. The present case report describes a patient with CAMK2B -related disorder confirmed by whole exome sequencing and adds to the current information in the literature. We review three case reports in literature with detailed descriptions of patients presenting with mutations in the CAMK2B gene. While there is a broad spectrum of phenotypic presentations, there appears to be an emerging neurobehavioral phenotype. Optimal management of patients will require attention to behavioral issues as well as involvement of neuropsychiatric expertise along with other supports for development and vision abnormalities.
ABSTRACT
BACKGROUND: The incidence of medium-chain acyl-CoA dehydrogenase deficiency (MCADD) was estimated using the Canadian Paediatric Surveillance Program (CPSP) in Canada over a three-year period. Data regarding mutations associated with MCADD cases were collected wherever available. METHODS: Data were collected over a 36-month period using a monthly mailed questionnaire distributed through the CPSP to more than 2500 Canadian paediatricians, medical geneticists and paediatric pathologists. RESULTS AND CONCLUSIONS: During the three years of MCADD surveillance, 46 confirmed cases out of a total of 71 reported cases were found - an average of approximately 15 cases per year. This rate is lower than the initial estimate of approximately 30 cases per year of MCADD in Canada, based on the reported incidence of MCADD in the literature of approximately one in 10,000 to one in 20,000. All cases ascertained by newborn screening were asymptomatic. There were two deaths, both in jurisdictions without newborn screening for MCADD. The data support population-based newborn screening for MCADD.
HISTORIQUE: Les chercheurs ont évalué l'incidence de déficit en acyl-coenzyme A déshydrogénase des acides gras à chaîne moyenne (DACAD) au Canada au moyen du Programme canadien de surveillance pédiatrique (PCSP), sur une période de trois ans. Dans la mesure du possible, ils ont amassé des données sur les mutations associées aux cas de DACAD. MÉTHODOLOGIE: Les chercheurs ont colligé des données sur une période de 36 mois au moyen de questionnaires mensuels postés par l'entremise du PCSP à plus de 2 500 pédiatres, généticiens médicaux et pathologistes pédiatres canadiens. RÉSULTATS ET CONCLUSIONS: Pendant les trois ans de surveillance du DACAD, les chercheurs ont recensé 46 cas confirmés sur un total de 71 cas signalés, soit une moyenne d'environ 15 cas par année. Ce taux est inférieur à l'évaluation initiale d'environ 30 cas de DACAD par année au Canada, établi d'après l'incidence d'environ un cas sur 10 000 à 20 000 habitants déterminée dans les publications. Tous les cas constatés par dépistage des nouveau-nés étaient asymptomatiques. On a constaté deux décès, tous deux dans des territoires de compétence ne disposant pas du dépistage du DACAD chez les nouveau-nés. Les données appuient le dépistage en population du DACAD chez les nouveau-nés.
ABSTRACT
BACKGROUND: Mucopolysaccharidosis type VI (MPS VI) is an inherited multisystem lysosomal disorder due to arylsulfatase B (ARSB) deficiency that leads to widespread accumulation of glycosaminoglycans (GAG), which are excreted in increased amounts in urine. MPS VI is characterized by progressive dysostosis multiplex, connective tissue and cardiac involvement, and hepatosplenomegaly. Enzyme replacement therapy (ERT) is available but requires life-long and costly intravenous infusions; moreover, it has limited efficacy on diseased skeleton and cardiac valves, compromised pulmonary function, and corneal opacities. METHODS: We enrolled nine patients with MPS VI 4 years of age or older in a phase 1/2 open-label gene therapy study. After ERT was interrupted, patients each received a single intravenous infusion of an adeno-associated viral vector serotype 8 expressing ARSB. Participants were sequentially enrolled in one of three dose cohorts: low (three patients), intermediate (two patients), or high (four patients). The primary outcome was safety; biochemical and clinical end points were secondary outcomes. RESULTS: The infusions occurred without severe adverse events attributable to the vector, meeting the prespecified end point. Participants in the low and intermediate dose cohorts displayed stable serum ARSB of approximately 20% of the mean healthy value but returned to ERT by 14 months after gene therapy because of increased urinary GAG. Participants in the high-dose cohort had sustained serum ARSB of 30% to 100% of the mean healthy value and a modest urinary GAG increase that did not reach a concentration at which ERT reintroduction was needed. In the high-dose group, there was no clinical deterioration for up to 2 years after gene therapy. CONCLUSIONS: Liver-directed gene therapy for participants with MPS VI did not have a dose-limiting side-effect and adverse event profile; high-dose treatment resulted in ARSB expression over at least 24 months with preliminary evidence of disease stabilization. (Funded by the Telethon Foundation ETS, the European Commission Seventh Framework Programme, and the Isaac Foundation; ClinicalTrials.gov number, NCT03173521; EudraCT number, 2016-002328-10.)
Subject(s)
Dependovirus , Genetic Therapy , Mucopolysaccharidosis VI , N-Acetylgalactosamine-4-Sulfatase , Humans , Genetic Therapy/methods , Mucopolysaccharidosis VI/therapy , Mucopolysaccharidosis VI/genetics , Mucopolysaccharidosis VI/urine , Male , Female , Dependovirus/genetics , Child , Adolescent , Child, Preschool , N-Acetylgalactosamine-4-Sulfatase/genetics , Adult , Young Adult , Genetic Vectors/administration & dosage , Liver/metabolism , Liver/pathology , Enzyme Replacement Therapy/methodsABSTRACT
UNLABELLED: We report the case of a 3-month-old boy who presented with a 3-day history of respiratory tract infection and poor feeding. He was incidentally found to have profound hypoglycaemia, high-anion-gap lactic acidosis, ketonuria, hyperlipidemia, hepatomegaly, growth failure and neutropenia. Glycogen storage disease type Ib (GSD Ib), an autosomal recessive metabolic defect of the microsomal transporter glucose-6-phosphate-translocase, was suspected and confirmed by genetic testing. Treatment consisted of initial intravenous glucose and fluids to correct his lactic acidosis, followed by a strict dietary protocol consisting of soy-based infant formula enriched with glucose polymers from cornstarch and overnight gastrostomy feeds. CONCLUSIONS: GSD I should be considered in all young children presenting with hypoglycaemia and lactic acidosis. Presence of neutropenia further confirms GSD Ib. Even critical hypoglycaemia can be clinically unapparent in affected children.
Subject(s)
Acidosis, Lactic/pathology , Glycogen Storage Disease Type I/complications , Hypoglycemia/etiology , Neutropenia/pathology , Age Factors , Antiporters/metabolism , Glycogen Storage Disease Type I/pathology , Granulocyte Colony-Stimulating Factor/metabolism , Humans , Hypoglycemia/diagnosis , Hypoglycemia/pathology , Infant , Male , Monosaccharide Transport Proteins/metabolism , Severity of Illness IndexSubject(s)
Fumarate Hydratase/deficiency , Metabolism, Inborn Errors/diagnosis , Metabolism, Inborn Errors/etiology , Muscle Hypotonia/diagnosis , Muscle Hypotonia/etiology , Psychomotor Disorders/diagnosis , Psychomotor Disorders/etiology , Alleles , Child, Preschool , Echocardiography , Energy Metabolism/genetics , Female , Genotype , Humans , In Situ Hybridization, Fluorescence , Karyotype , Magnetic Resonance Imaging , Pedigree , Phenotype , Symptom Assessment , Exome SequencingABSTRACT
OBJECTIVES: A recessively inherited defect leading to deficiency of the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR) underlies one form of hyperhomocysteinemia. We describe the association of severe MTHFR deficiency and neurological manifestations with particular attention to neurodevelopment and evolution of epileptic seizures. METHODS: Case study and review of literature. RESULTS: A 9 year old female infant born to Caucasian non-consanguineous parents presented with infantile spasms and developmental regression in the first year. The biochemical profile of low plasma methionine (below detectable limits), and slightly elevated homocystine (3 µmol/L (0-trace) and homocystinuria (234 µmol/gm creatinine) (0-trace amounts) was suggestive of a disturbance in homocysteine metabolism. Plasma homocysteine measurements (30.7 µmol/L, normal <13.5 µmol/L) confirmed hyperhomocysteinemia. Enzyme assay in skin fibroblasts confirmed severe MTHFR deficiency (patient 0.92, control 13.3±4.6nmol/mg/h). Molecular genetic studies identified compound heterozygosity for 2 variant polymorphisms (c.677C>T, and c.1298A>C) and a splicing mutation (c.1348+1G>A). This is a novel mutation that removes a splice site at the end of exon 7 resulting in a premature stop codon that truncates the protein, losing exons 8-11. CSF neurotransmitter analysis showed an extremely low level of 5-methyl tetrahydrofolate of <5 (40-128 nmol/L). The course of epilepsy has been characterized by progression to severe epileptic encephalopathy. Periventricular white matter change consistent with demyelination is seen on MR imaging. Treatment protocols include; oral betaine, supplementation with methionine, folic acid, and 5-methyltetrahydrofolate with questionable benefit. Epileptic seizures remain pharmacoresistant to antiepileptic medications singly and in combinations. Frequent bouts of status epilepticus have led to multiple hospitalizations, and neurosurgical interventions (corpus callosotomy, vagal nerve stimulation). At age 9 years, the patient remains severely impaired by vertebral compressive and limb fractures secondary to severe osteoporosis. CONCLUSION: Severe MTHFR deficiency is an important diagnostic consideration in infantile epileptic encephalopathies. Early diagnosis and specific treatment interventions are possible. Further research is needed into effective treatment of epilepsy and prevention of complications in this disorder. Genotype and phenotype correlations will be explored in the light of available biochemical and molecular genetic data.