Ayelet Zerem

Paroxysmal tonic upward gaze as a presentation of de-novo mutations in CACNA1A

OBJECTIVE Paroxysmal tonic upward gaze was initially described as a benign phenomenon with negative investigations and eventual complete resolution of symptoms. Later publications demonstrated that a similar clinical picture may arise from structural brain lesions, channelopathies, neurotransmitter disorders, and epileptic seizures. CACNA1A related disorders manifest as a wide spectrum of paroxysmal neurological disorders: episodic ataxia 2, hemiplegic migraine, benign paroxysmal torticollis of infancy, and paroxysmal vertigo. Paroxysmal tonic upward gaze as a phenomenon in patients with mutations in the CACNA1A gene has only been reported once. METHODS We describe three patients with multiple episodes of paroxysmal tonic upward gaze that appeared during the first months of life. In addition the patients demonstrated motor and language delay and cerebellar ataxia. A sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the other patients were performed. RESULTS Sequence analysis of the CACNA1A gene in one patient and whole exome sequencing in the two other patients revealed 3 different de-novo mutations in the CACNA1A gene. CONCLUSION CACNA1A mutations should be evaluated in infants and young children with paroxysmal tonic upgaze especially if associated with developmental delay, cerebellar signs, and other types of paroxysmal event.

Heterozygous Mutations in the ADCK3 Gene in Siblings with Cerebellar Atrophy and Extreme Phenotypic Variability.

UNLABELLED We describe a highly variable clinical presentation of cerebellar ataxia in two sisters. The younger sister demonstrates early onset rapidly progressive cerebellar ataxia accompanied by motor and nonmotor cerebellar features, as well as cognitive decline and psychiatric problems. Mitochondrial respiratory chain enzyme analysis in muscle showed a decrease in complex I + III. Progressive cerebellar atrophy was demonstrated on serial brain MR imaging. Coenzyme Q10 (CoQ10) supplementation, started at the age of 5 years, led to a significant improvement in motor and cognitive abilities with partial amelioration of the cerebellar signs. Discontinuation of this treatment resulted in worsening of the ataxia, cognitive decline, and severe depression.The older sister, who is 32 years old, has nonprogressive dysarthria and clumsiness from the age of 10 years and MRI reveals cerebellar atrophy.Exome sequencing identified compound heterozygosity for a known (p. Thr584delACC (c.1750_1752delACC)) and a novel (p.P502R) mutation in the ACDK3 gene. CONCLUSIONS Patients with primary CoQ10 deficiency due to ADCK3 mutations can demonstrate a wide spectrum of clinical presentations even in the same family. It is difficult to diagnose CoQ10 deficiency based solely on the clinical presentation.Exome sequencing can provide the molecular diagnosis but since it is expensive and not readily available, we recommend a trial of CoQ10 treatment in patients with ataxia and cerebellar atrophy even before confirmation of the molecular diagnosis.

The molecular and phenotypic spectrum of IQSEC2-related epilepsy.

IQSEC2 is an X‐linked gene associated with intellectual disability (ID) and epilepsy. Herein we characterize the epilepsy/epileptic encephalopathy of patients with IQSEC2 pathogenic variants.

Primary and maternal 3-methylcrotonyl-CoA carboxylase deficiency: insights from the Israel newborn screening program

Background3-Methylcrotonyl-CoA carboxylase deficiency (3MCCD) is an inborn error of leucine catabolism. Tandem mass spectrometry newborn screening (NBS) programs worldwide confirmed 3MCCD to be the most common organic aciduria and a relatively benign disorder with favorable outcome. In addition, several asymptomatic 3MCCD mothers were initially identified following abnormal screening of their healthy babies and were appropriately termed maternal 3MCCD.MethodsThis is a retrospective study that summarizes all the clinical, biochemical, and genetic data collected by questionnaires of all 3MCCD individuals that were identified by the extended Israeli NBS program since its introduction in 2009 including maternal 3MCCD cases.ResultsA total of 36 3MCCD subjects were diagnosed within the 50-month study period; 16 were classified primary and 20 maternal cases. Four additional 3MCCD individuals were identified following sibling screening. All maternal 3MCCD cases were asymptomatic except for one mother who manifested childhood hypotonia. Most of the primary 3MCCD individuals were asymptomatic except for two whose condition was also complicated by severe prematurity. Initial dried blood spot (DBS) free carnitine was significantly lower in neonates born to 3MCCD mothers compared with newborns with primary 3MCCD (p = 0.0009). Most of the mutations identified in the MCCC1 and MCCC2 genes were missense, five of them were novel.ConclusionsMaternal 3MCCD is more common than previously thought and its presence may be initially indicated by low DBS free carnitine levels. Our findings provide additional confirmation of the benign nature of 3MCCD and we suggest to exclude this disorder from NBS programs.

Paternal germline mosaicism of a SCN2A mutation results in Ohtahara syndrome in half siblings

Ohtahara syndrome is a devastating early infantile epileptic encephalopathy caused by mutations in different genes. We describe a patient with Ohtahara syndrome who presented on the first day of life with refractory tonic seizures and a suppression-burst pattern on EEG. The patient developed severe microcephaly, and never achieved any developmental milestones. He died at the age of 5 years. A de novo missense mutation (c. 4007C>A, p.S1336Y) in SCN2A was found. Interestingly, the father has another son with Ohtahara syndrome from a different mother. The half brother carries the same SCN2A mutation, strongly suggesting paternal gonadal mosaicism of the mutation. The broad clinical spectrum of SCN2A mutations now includes Ohtahara syndrome. This is the first report of familial Ohtahara syndrome due to a germline mosaic SCN2A mutation. Somatic mosaicism, including germline, has been described in several epileptic encephalopathies such as Dravet syndrome, KCNQ2 neonatal epileptic encephalopathy, SCN8A epileptic encephalopathy and STXBP1 related Ohtahara syndrome. Mosaicism should be considered as one of the important inheritance patterns when counseling parents with a child with these devastating diseases.

Utility of Whole Exome Sequencing for Genetic Diagnosis of Previously Undiagnosed Pediatric Neurology Patients

Whole exome sequencing enables scanning a large number of genes for relatively low costs. The authors investigate its use for previously undiagnosed pediatric neurological patients. This retrospective cohort study performed whole exome sequencing on 57 patients of “Magen” neurogenetic clinics, with unknown diagnoses despite previous workup. The authors report on clinical features, causative genes, and treatment modifications and provide an analysis of whole exome sequencing utility per primary clinical feature. A causative gene was identified in 49.1% of patients, of which 17 had an autosomal dominant mutation, 9 autosomal recessive, and 2 X-linked. The highest rate of positive diagnosis was found for patients with developmental delay, ataxia, or suspected neuromuscular disease. Whole exome sequencing warranted a definitive change of treatment for 5 patients. Genetic databases were updated accordingly. In conclusion, whole exome sequencing is useful in obtaining a high detection rate for previously undiagnosed disorders. Use of this technique could affect diagnosis, treatment, and prognostics for both patients and relatives.

Mosaic marker chromosome 16 resulting in 16q11.2–q12.1 gain in a child with intellectual disability, microcephaly, and cerebellar cortical dysplasia†

Proximal duplications of the long arm of chromosome 16 are rare and only a few patients have been reported. Clinically, the patients do not have a distinctive syndromic appearance; however they all show some degree of intellectual disability and most have severely delayed speech development. We report on a child presenting with mild‐to‐moderate intellectual disability, microcephaly, language dyspraxia, and mild dysmorphisms who was found to have a mosaic gain of chromosome 16q (16q11.2–16q12.1). Magnetic resonance imaging done at the age of 4 years demonstrated cerebellar cortical dysplasia involving the vermis and hemispheres. This is the first report of cerebellar anomalies in a patient with partial trisomy 16q. The genes ZNF423 and CBLN1 found in the duplicated region play a role in the development of the cerebellum and may be responsible for the cerebellar cortical dysplasia.

Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies

Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.

Spontaneously regressing leukoencephalopathy with bilateral temporal cysts in congenital rubella infection

Very little is known regarding neuroimaging findings in patients with congenital rubella syndrome. We report a 1.9-year-old boy with congenital rubella syndrome who presented in the neonatal period with severe multisystem involvement and diffuse leukoencephalopathy with subcortical anterior temporal cysts, which showed spontaneous improvement during a period of 3 years.

Dominantly Inherited Nonprogressive Cerebellar Hypoplasia Identified In Utero

Cerebellar hypoplasia is the hallmark of a heterogeneous group of disorders that are caused by genetic and metabolic disorders. Prenatal identification of cerebellar hypoplasia and accurate prediction of outcome are challenging. Autosomal dominant nonprogressive cerebellar ataxia is a rare disorder that typically presents with early hypotonia and delayed motor milestones followed by the onset of mild ataxia and occasionally cognitive impairment. We present a case of a mother and her female fetus. Fetal sonography and magnetic resonance imaging (MRI) showed generalized cerebellar hypoplasia. The mother had mild learning difficulties and clinically showed minor features of cerebellar ataxia. Her MRI also demonstrated extreme cerebellar hypoplasia. The diagnosis of autosomal dominant nonprogressive cerebellar ataxia was suggested. This is the first report of prenatal diagnosis of autosomal dominant nonprogressive cerebellar ataxia. We recommend obtaining a family history, examining the parents, and when appropriate obtaining an MRI before counseling parents of a fetus with a brain malformation.