Marina Michelson | Tel Aviv University (original) (raw)

Papers by Marina Michelson

Clinical genetics, Feb 13, 2024

American Journal of Medical Genetics, Mar 21, 2022

Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congeni... more Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema–Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants inFOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1–q24.2. This report extends the phenotype of both 16q24.1–q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3′‐UTR part ofFOXC2.

American Journal of Medical Genetics Part A, 2022

Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congeni... more Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema–Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants inFOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1–q24.2. This report extends the phenotype of both 16q24.1–q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3′‐UTR part ofFOXC2.

Journal of Inherited Metabolic Disease, 1999

The prevalence of 3‐methylglutaconic aciduria was evaluated among children with developmental lan... more The prevalence of 3‐methylglutaconic aciduria was evaluated among children with developmental language disorders. A urine specimen was obtained from 40 children referred for developmental language delay to the Tel‐Aviv Child Development Center during 12/96–6/97 and from 50 age‐matched controls. Urine organic acids were analysed by gas chromatography–mass spectrometry. Urinary 3‐methylglutaconic acid was quantified. A mildly increased excretion of 3‐methylglutaconic acid was found in 8 children with developmental language delay. The combined excretion of 3‐methylglutaconic and 3‐methylglutaric acid was increased in 9 patients. There were no differences in the excretion of other organic acids. The patients with elevated 3‐methylglutaconic acid did not differ from the other patients with developmentallanguage disorders in any of the parameters evaluated. Mildly elevated urinary levels of 3‐methylglutaconic acid may be a marker of a still undefined metabolic disorder presenting with dev...

Journal of Child Neurology, 2019

PTEN (Phosphatase and Tensin Homolog on chromosome TEN) encodes a vastly expressed tumor suppress... more PTEN (Phosphatase and Tensin Homolog on chromosome TEN) encodes a vastly expressed tumor suppressor protein that antagonizes the PI3 K signaling pathway and alters the MTOR pathway. Mutations in PTEN have been described in association with a number of syndromes including PTEN hamartoma-tumor syndrome, macrocephaly/autism, and juvenile polyposis of infancy. Although there is a wide variability in the clinical and radiologic presentations of PTEN-related phenotypes, the most consistent features include macrocephaly and increased tumorigenesis. Intracranial hypertension may be idiopathic or secondary to multiple etiologies. We describe 2 siblings harboring a PTEN mutation who presented with macrocephaly and intracranial hypertension. Repeat brain MRIs were normal in both. Acetazolamide treatment normalized intracranial pressure, but several trials of medication tapering led to recurrence of intracranial hypertension symptoms. The clinical presentation of our patients expands the PTEN-r...

Pediatric Rheumatology, 2015

European Journal of Paediatric Neurology, 2015

Objective Partial deletions of the gene encoding the neuronal splicing regulator RBFOX1 have been... more Objective Partial deletions of the gene encoding the neuronal splicing regulator RBFOX1 have been reported in a range of neurodevelopmental diseases, including idiopathic generalized epilepsy, Rolandic epilepsy (RE), Autosomal dominant lateral temporal epilepsy (ADLTE) or idiopathic generalized epilepsy (IGE). Patients often exhibit severe co-morbid neuro-developmental disorders such as intellectual disability (ID) and Autism spectrum disorders (ASD) or microcephaly. Heterozygous RBFOX1 knockout mouse models demonstrate deregulated splicing, disrupting genes involved in synaptic transmission and membrane excitability leading to increased susceptibility for seizure events. All patients reported so far have a hemizygous deletion/mutation and the transmitting parents in most cases were asymptomatic. We report a female toddler, that first presented with adversive seizures at four months of age, progressing to intractable epilepsy. EEG demonstrated generalized spike & wave activity. Currently at the age of thirty months she has profound ID and progressive post-natal microcephaly. Extensive diagnostic workup was uninformative – including whole exome sequencing (WES) for known epilepsy mutations. Brain MRI demonstrated non-specific findings. Her parents are first cousins of Arab origin. Ten family members are noted for epilepsy, intellectual disability of different severities and autism, however none has the same severe presentation as the patient. Methods and results Chromosomal micro-array analysis (CMA) revealed a 426 KB homozygous deletion in chromosome 16p13.3 at the 5' UTR end of the RBFOX1 gene. The asymptomatic parents are heterozygous for the deletion. Conclusion This is the first case of a homozygous partial deletion of the RBFOX1 gene in a toddler suffering from epileptic encephalopathy with profound ID and progressive postnatal microcephaly detected by CMA. Our case strengthens the association of partial RBFOX1 deletions in neurodevelopmental diseases and extends the RBFOX1-related phenotypic spectrum.

European Journal of Paediatric Neurology, 2015

European Journal of Paediatric Neurology, 2015

ARSACS (autosomal-recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorde... more ARSACS (autosomal-recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorder caused by SACS gene mutations and characterized by a triad of symptoms: early-onset cerebellar ataxia, spasticity and peripheral neuropathy. A characteristic retinal nerve fiber hypertrophy has been reported in several individuals with ARSACS. We describe a patient with a unique clinical presentation of ataxia, nystagmus, dysarthria, hearing impairment, and retinal degeneration. Whole-exome-sequencing was performed as well as morphological studies in the patient's fibroblasts. A compound heterozygosity for a novel D3269N and N2380K mutations in the SACS gene was found. The parents are carriers. Morphological studies revealed a dramatic decrease in the number of cell mitochondria as well as a difference in mitochondrial network morphology. Retinal degeneration has never been reported in ARSACS. Since sacsin is involved in the mitochondrial fusion-fission process, we speculate that defected fission process may be responsible for an impaired mitochondrial function and retinal degeneration. Our patient has a unique clinical presentation of SACS mutations inconsistent with the classic ARSACS triad but also different from the "atypical" presentations described in the literature. Further studies are necessary to clarify the factors that modify the SACS related phenotype.

Neurology, 2001

Brain malformations are caused by a disruption in the sequence of normal development by various e... more Brain malformations are caused by a disruption in the sequence of normal development by various environmental or genetic factors. By modifying the intrauterine milieu, inborn errors of metabolism may cause brain dysgenesis. However, this association is typically described in single case reports. The authors review the relationship between brain dysgenesis and specific inborn errors of metabolism. Peroxisomal disorders and fatty acid oxidation defects can produce migration defects. Pyruvate dehydrogenase deficiency, nonketotic hyperglycinemia, and maternal phenylketonuria preferentially cause a dysgenetic corpus callosum. Abnormal metabolism of folic acid causes neural tube defects, whereas defects in cholesterol metabolism may produce holoprosencephaly. Various mechanisms have been proposed to explain abnormal brain development in inborn errors of metabolism: production of a toxic or energy-deficient intrauterine milieu, modification of the content and function of membranes, or disturbance of the normal expression of intrauterine genes responsible for morphogenesis. The recognition of a metabolic disorder as the cause of the brain malformation has implications for both the care of the patient and for genetic counseling to prevent recurrence in subsequent pregnancies.

Journal of Genetic Counseling, 2011

Facioscapulohumeral muscular dystrophy (FSHD), is a dominantly inherited, late onset, progressive... more Facioscapulohumeral muscular dystrophy (FSHD), is a dominantly inherited, late onset, progressive disease. At present, no treatment or prevention of symptoms are available. There is considerable clinical variability, even within families. The gene whose defect causes FSHD has not been identified, but molecular diagnosis can be made by analyzing D4Z4 repeat length on chromosome 4q35. The results can support or rule out the clinical diagnosis of FSHD, but there are also "gray zone", non-conclusive results. During the years 2000-6, 66 individuals (including 7 asymptomatic individuals), were tested in our institute for D4Z4 repeat number. In 77% of the cases the results were conclusive: two thirds of them supported a diagnosis of FSHD while in a third this diagnosis was ruled out. In 23% the results were in the gray zone. Cognitive involvement was rare, occurring only when the D4Z4 repeat size was very small (<15 kb). Maximal utilization of the existing molecular test for FSHD demands detailed clinical and family pedigree information. We recommend that comprehensive genetic counseling always be given before and after molecular testing for FSHD, in addition to the neurological follow-up. Presymptomatic testing should only be offered when complete molecular evaluation can be offered, including 4qA and 4qB variant analysis.

Journal of Child Neurology, 2010

The CACNA1A gene encodes the pore forming alpha-1A subunit of neuronal voltage-dependant P/Q-type... more The CACNA1A gene encodes the pore forming alpha-1A subunit of neuronal voltage-dependant P/Q-type Ca 2+ channels. Mutations in this gene result in clinical heterogeneity, and present with either chronic progressive symptoms, paroxysmal events, or both, with clinical overlap among the different phenotypes. The authors describe a seven year-old boy with mental retardation and congenital cerebellar ataxia that developed dyskinesia at the age of a few months, and recurrent episodes of coma following mild head trauma associated with motor and autonomic signs, from the second year of life. An extensive metabolic evaluation, interictal electroencephalography (EEG), and muscle biopsy were normal. Brain magnetic resonance imaging (MRI) during one of these episodes revealed edema of the right hemisphere and cerebellar atrophy. Genetic testing revealed a R1350Q mutation in the CACNA1A gene. This is a novel de novo mutation.Congenital cerebellar ataxia can be a result of CACNA1A mutations, espe...

European Journal of Paediatric Neurology, 2012

European Journal of Paediatric Neurology, 2009

European Journal of Paediatric Neurology, 1999

European Journal of Paediatric Neurology, 2011

Various rearrangements involve the proximal long arm of chromosome 15, including deletions, dupli... more Various rearrangements involve the proximal long arm of chromosome 15, including deletions, duplications, translocations, inversions and supernumerary marker chromosome of an inverted duplication. The large marker 15, that contains the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) chromosome region, is usually associated with an abnormal phenotype of moderate to severe mental retardation, seizures, poor motor coordination, early-onset central hypotonia, autism and autistic-like behavior, schizophrenia and mild dysmorphic features. We report a ten year-old girl with normal intelligence prior to the onset of seizures, who developed severe intractable epilepsy at the age of seven years. Family history was significant for a mother with recurrent episodes of acute psychosis. The patient's and mother's karyotype revealed 47,XX+m. Array comparative genomic hybridization (A-CGH) identified a gain of 13 BAC clones from 15q11.2 through 15q13.1, which was then confirmed by FISH to be part of the marker chromosome. This duplicated region contains the SNRPN/UBE3A locus. This case demonstrates that a duplication of 15q11-13 can present differently in the same family either as intractable epilepsy or as a psychiatric illness and that intelligence can be preserved. We suggest that CGH microarray should be performed in cases with intractable epilepsy or schizophrenia, with or without mental retardation.

European Journal of Paediatric Neurology, 2008

Isolated mitochondrial myopathies (IMM) are either due to primary defects in mtDNA, in nuclear ge... more Isolated mitochondrial myopathies (IMM) are either due to primary defects in mtDNA, in nuclear genes that control mtDNA abundance and structure such as thymidine kinase 2 (TK2), or due to CoQ deficiency. Defects in the TK2 gene have been found to be associated with mtDNA depletion attributed to a depleted mitochondrial dNTP pool in non-dividing cells. We report an unusual case of IMM, homozygous for the H90N mutation in the TK2 gene but unlike other cases with the same mutation, does not demonstrate mtDNA depletion. The patient's clinical course is relatively mild and a muscle biopsy showed ragged red muscle fibers with a mild decrease in complexes I and an increase in complexes IV and II activities. This report extends the phenotypic expression of TK2 defects and suggests that all patients who present with an IMM even with normal quantities of mtDNA should be screened for TK2 mutations.

American Journal of Medical Genetics Part A, 2012

Interstitial deletions of the long arm of chromosome 6 are rare. Clinically, this is a recognizab... more Interstitial deletions of the long arm of chromosome 6 are rare. Clinically, this is a recognizable microdeletion syndrome associated with intellectual disability (ID), acquired microcephaly, typical dysmorphic features, structural anomalies of the brain, and nonspecific multiple organ anomalies. Most of the reported cases have cytogenetically visible interstitial deletions or subtelomeric microdeletions. We report on a boy with global developmental delay, distinct dysmorphic features, dysgenesis of the corpus callosum, limb anomalies, and genital hypoplasia who has a small interstitial deletion of the long arm of chromosome 6 detected by comparative genomic hybridization (CGH). The deleted region spans around 1 Mb of DNA and contains only two coding genes, ARID1B and ZDHHC14. To the best of our knowledge, this case represents the typical phenotype with the smallest deletion reported so far. We discuss the possible role of these genes in the phenotypic manifestations.

Clinical genetics, Feb 13, 2024

American Journal of Medical Genetics, Mar 21, 2022

Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congeni... more Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema–Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants inFOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1–q24.2. This report extends the phenotype of both 16q24.1–q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3′‐UTR part ofFOXC2.

American Journal of Medical Genetics Part A, 2022

Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congeni... more Interstitial deletions of 16q24.1–q24.2 are associated with alveolar capillary dysplasia, congenital renal malformations, neurodevelopmental disorders, and congenital abnormalities. Lymphedema–Distichiasis syndrome (LDS; OMIM # 153400) is a dominant condition caused by heterozygous pathogenic variants inFOXC2. Usually, lymphedema and distichiasis occur in puberty or later on, and affected individuals typically achieve normal developmental milestones. Here, we describe a boy with congenital lymphedema, distichiasis, bilateral hydronephrosis, and global developmental delay, with a de novo microdeletion of 894 kb at 16q24.1–q24.2. This report extends the phenotype of both 16q24.1–q24.2 microdeletion syndrome and of LDS. Interestingly, the deletion involves only the 3′‐UTR part ofFOXC2.

Journal of Inherited Metabolic Disease, 1999

The prevalence of 3‐methylglutaconic aciduria was evaluated among children with developmental lan... more The prevalence of 3‐methylglutaconic aciduria was evaluated among children with developmental language disorders. A urine specimen was obtained from 40 children referred for developmental language delay to the Tel‐Aviv Child Development Center during 12/96–6/97 and from 50 age‐matched controls. Urine organic acids were analysed by gas chromatography–mass spectrometry. Urinary 3‐methylglutaconic acid was quantified. A mildly increased excretion of 3‐methylglutaconic acid was found in 8 children with developmental language delay. The combined excretion of 3‐methylglutaconic and 3‐methylglutaric acid was increased in 9 patients. There were no differences in the excretion of other organic acids. The patients with elevated 3‐methylglutaconic acid did not differ from the other patients with developmentallanguage disorders in any of the parameters evaluated. Mildly elevated urinary levels of 3‐methylglutaconic acid may be a marker of a still undefined metabolic disorder presenting with dev...

Journal of Child Neurology, 2019

PTEN (Phosphatase and Tensin Homolog on chromosome TEN) encodes a vastly expressed tumor suppress... more PTEN (Phosphatase and Tensin Homolog on chromosome TEN) encodes a vastly expressed tumor suppressor protein that antagonizes the PI3 K signaling pathway and alters the MTOR pathway. Mutations in PTEN have been described in association with a number of syndromes including PTEN hamartoma-tumor syndrome, macrocephaly/autism, and juvenile polyposis of infancy. Although there is a wide variability in the clinical and radiologic presentations of PTEN-related phenotypes, the most consistent features include macrocephaly and increased tumorigenesis. Intracranial hypertension may be idiopathic or secondary to multiple etiologies. We describe 2 siblings harboring a PTEN mutation who presented with macrocephaly and intracranial hypertension. Repeat brain MRIs were normal in both. Acetazolamide treatment normalized intracranial pressure, but several trials of medication tapering led to recurrence of intracranial hypertension symptoms. The clinical presentation of our patients expands the PTEN-r...

Pediatric Rheumatology, 2015

European Journal of Paediatric Neurology, 2015

Objective Partial deletions of the gene encoding the neuronal splicing regulator RBFOX1 have been... more Objective Partial deletions of the gene encoding the neuronal splicing regulator RBFOX1 have been reported in a range of neurodevelopmental diseases, including idiopathic generalized epilepsy, Rolandic epilepsy (RE), Autosomal dominant lateral temporal epilepsy (ADLTE) or idiopathic generalized epilepsy (IGE). Patients often exhibit severe co-morbid neuro-developmental disorders such as intellectual disability (ID) and Autism spectrum disorders (ASD) or microcephaly. Heterozygous RBFOX1 knockout mouse models demonstrate deregulated splicing, disrupting genes involved in synaptic transmission and membrane excitability leading to increased susceptibility for seizure events. All patients reported so far have a hemizygous deletion/mutation and the transmitting parents in most cases were asymptomatic. We report a female toddler, that first presented with adversive seizures at four months of age, progressing to intractable epilepsy. EEG demonstrated generalized spike & wave activity. Currently at the age of thirty months she has profound ID and progressive post-natal microcephaly. Extensive diagnostic workup was uninformative – including whole exome sequencing (WES) for known epilepsy mutations. Brain MRI demonstrated non-specific findings. Her parents are first cousins of Arab origin. Ten family members are noted for epilepsy, intellectual disability of different severities and autism, however none has the same severe presentation as the patient. Methods and results Chromosomal micro-array analysis (CMA) revealed a 426 KB homozygous deletion in chromosome 16p13.3 at the 5' UTR end of the RBFOX1 gene. The asymptomatic parents are heterozygous for the deletion. Conclusion This is the first case of a homozygous partial deletion of the RBFOX1 gene in a toddler suffering from epileptic encephalopathy with profound ID and progressive postnatal microcephaly detected by CMA. Our case strengthens the association of partial RBFOX1 deletions in neurodevelopmental diseases and extends the RBFOX1-related phenotypic spectrum.

European Journal of Paediatric Neurology, 2015

European Journal of Paediatric Neurology, 2015

ARSACS (autosomal-recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorde... more ARSACS (autosomal-recessive spastic ataxia of Charlevoix-Saguenay) is a neurodegenerative disorder caused by SACS gene mutations and characterized by a triad of symptoms: early-onset cerebellar ataxia, spasticity and peripheral neuropathy. A characteristic retinal nerve fiber hypertrophy has been reported in several individuals with ARSACS. We describe a patient with a unique clinical presentation of ataxia, nystagmus, dysarthria, hearing impairment, and retinal degeneration. Whole-exome-sequencing was performed as well as morphological studies in the patient's fibroblasts. A compound heterozygosity for a novel D3269N and N2380K mutations in the SACS gene was found. The parents are carriers. Morphological studies revealed a dramatic decrease in the number of cell mitochondria as well as a difference in mitochondrial network morphology. Retinal degeneration has never been reported in ARSACS. Since sacsin is involved in the mitochondrial fusion-fission process, we speculate that defected fission process may be responsible for an impaired mitochondrial function and retinal degeneration. Our patient has a unique clinical presentation of SACS mutations inconsistent with the classic ARSACS triad but also different from the "atypical" presentations described in the literature. Further studies are necessary to clarify the factors that modify the SACS related phenotype.

Neurology, 2001

Brain malformations are caused by a disruption in the sequence of normal development by various e... more Brain malformations are caused by a disruption in the sequence of normal development by various environmental or genetic factors. By modifying the intrauterine milieu, inborn errors of metabolism may cause brain dysgenesis. However, this association is typically described in single case reports. The authors review the relationship between brain dysgenesis and specific inborn errors of metabolism. Peroxisomal disorders and fatty acid oxidation defects can produce migration defects. Pyruvate dehydrogenase deficiency, nonketotic hyperglycinemia, and maternal phenylketonuria preferentially cause a dysgenetic corpus callosum. Abnormal metabolism of folic acid causes neural tube defects, whereas defects in cholesterol metabolism may produce holoprosencephaly. Various mechanisms have been proposed to explain abnormal brain development in inborn errors of metabolism: production of a toxic or energy-deficient intrauterine milieu, modification of the content and function of membranes, or disturbance of the normal expression of intrauterine genes responsible for morphogenesis. The recognition of a metabolic disorder as the cause of the brain malformation has implications for both the care of the patient and for genetic counseling to prevent recurrence in subsequent pregnancies.

Journal of Genetic Counseling, 2011

Facioscapulohumeral muscular dystrophy (FSHD), is a dominantly inherited, late onset, progressive... more Facioscapulohumeral muscular dystrophy (FSHD), is a dominantly inherited, late onset, progressive disease. At present, no treatment or prevention of symptoms are available. There is considerable clinical variability, even within families. The gene whose defect causes FSHD has not been identified, but molecular diagnosis can be made by analyzing D4Z4 repeat length on chromosome 4q35. The results can support or rule out the clinical diagnosis of FSHD, but there are also "gray zone", non-conclusive results. During the years 2000-6, 66 individuals (including 7 asymptomatic individuals), were tested in our institute for D4Z4 repeat number. In 77% of the cases the results were conclusive: two thirds of them supported a diagnosis of FSHD while in a third this diagnosis was ruled out. In 23% the results were in the gray zone. Cognitive involvement was rare, occurring only when the D4Z4 repeat size was very small (<15 kb). Maximal utilization of the existing molecular test for FSHD demands detailed clinical and family pedigree information. We recommend that comprehensive genetic counseling always be given before and after molecular testing for FSHD, in addition to the neurological follow-up. Presymptomatic testing should only be offered when complete molecular evaluation can be offered, including 4qA and 4qB variant analysis.

Journal of Child Neurology, 2010

The CACNA1A gene encodes the pore forming alpha-1A subunit of neuronal voltage-dependant P/Q-type... more The CACNA1A gene encodes the pore forming alpha-1A subunit of neuronal voltage-dependant P/Q-type Ca 2+ channels. Mutations in this gene result in clinical heterogeneity, and present with either chronic progressive symptoms, paroxysmal events, or both, with clinical overlap among the different phenotypes. The authors describe a seven year-old boy with mental retardation and congenital cerebellar ataxia that developed dyskinesia at the age of a few months, and recurrent episodes of coma following mild head trauma associated with motor and autonomic signs, from the second year of life. An extensive metabolic evaluation, interictal electroencephalography (EEG), and muscle biopsy were normal. Brain magnetic resonance imaging (MRI) during one of these episodes revealed edema of the right hemisphere and cerebellar atrophy. Genetic testing revealed a R1350Q mutation in the CACNA1A gene. This is a novel de novo mutation.Congenital cerebellar ataxia can be a result of CACNA1A mutations, espe...

European Journal of Paediatric Neurology, 2012

European Journal of Paediatric Neurology, 2009

European Journal of Paediatric Neurology, 1999

European Journal of Paediatric Neurology, 2011

Various rearrangements involve the proximal long arm of chromosome 15, including deletions, dupli... more Various rearrangements involve the proximal long arm of chromosome 15, including deletions, duplications, translocations, inversions and supernumerary marker chromosome of an inverted duplication. The large marker 15, that contains the Prader-Willi syndrome (PWS)/Angelman syndrome (AS) chromosome region, is usually associated with an abnormal phenotype of moderate to severe mental retardation, seizures, poor motor coordination, early-onset central hypotonia, autism and autistic-like behavior, schizophrenia and mild dysmorphic features. We report a ten year-old girl with normal intelligence prior to the onset of seizures, who developed severe intractable epilepsy at the age of seven years. Family history was significant for a mother with recurrent episodes of acute psychosis. The patient's and mother's karyotype revealed 47,XX+m. Array comparative genomic hybridization (A-CGH) identified a gain of 13 BAC clones from 15q11.2 through 15q13.1, which was then confirmed by FISH to be part of the marker chromosome. This duplicated region contains the SNRPN/UBE3A locus. This case demonstrates that a duplication of 15q11-13 can present differently in the same family either as intractable epilepsy or as a psychiatric illness and that intelligence can be preserved. We suggest that CGH microarray should be performed in cases with intractable epilepsy or schizophrenia, with or without mental retardation.

European Journal of Paediatric Neurology, 2008

Isolated mitochondrial myopathies (IMM) are either due to primary defects in mtDNA, in nuclear ge... more Isolated mitochondrial myopathies (IMM) are either due to primary defects in mtDNA, in nuclear genes that control mtDNA abundance and structure such as thymidine kinase 2 (TK2), or due to CoQ deficiency. Defects in the TK2 gene have been found to be associated with mtDNA depletion attributed to a depleted mitochondrial dNTP pool in non-dividing cells. We report an unusual case of IMM, homozygous for the H90N mutation in the TK2 gene but unlike other cases with the same mutation, does not demonstrate mtDNA depletion. The patient's clinical course is relatively mild and a muscle biopsy showed ragged red muscle fibers with a mild decrease in complexes I and an increase in complexes IV and II activities. This report extends the phenotypic expression of TK2 defects and suggests that all patients who present with an IMM even with normal quantities of mtDNA should be screened for TK2 mutations.

American Journal of Medical Genetics Part A, 2012

Interstitial deletions of the long arm of chromosome 6 are rare. Clinically, this is a recognizab... more Interstitial deletions of the long arm of chromosome 6 are rare. Clinically, this is a recognizable microdeletion syndrome associated with intellectual disability (ID), acquired microcephaly, typical dysmorphic features, structural anomalies of the brain, and nonspecific multiple organ anomalies. Most of the reported cases have cytogenetically visible interstitial deletions or subtelomeric microdeletions. We report on a boy with global developmental delay, distinct dysmorphic features, dysgenesis of the corpus callosum, limb anomalies, and genital hypoplasia who has a small interstitial deletion of the long arm of chromosome 6 detected by comparative genomic hybridization (CGH). The deleted region spans around 1 Mb of DNA and contains only two coding genes, ARID1B and ZDHHC14. To the best of our knowledge, this case represents the typical phenotype with the smallest deletion reported so far. We discuss the possible role of these genes in the phenotypic manifestations.