RESUMEN
Hypomyelination and congenital cataract (HCC) is characterized by congenital cataract, progressive neurologic impairment, and diffuse myelin deficiency. This autosomal recessive disorder is caused by homozygous variant in the FAM126A gene. Five consanguineous Tunisian patients, belonging to three unrelated families, underwent routine blood tests, electroneuromyography, and magnetic resonance imaging of the brain. The direct sequencing of FAM126A exons was performed for the patients and their relatives. We summarized the 30 previously published HCC cases. All of our patients were carriers of a previously reported c.414 + 1G > T (IVS5 + 1G > T) variant, but the clinical spectrum was variable. Despite the absence of a phenotype-genotype correlation in HCC disease, screening of this splice site variant should be performed in family members at risk.
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Catarata , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias , Catarata/congénito , Catarata/diagnóstico por imagen , Catarata/genética , Consanguinidad , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/diagnóstico por imagen , Enfermedades Desmielinizantes del Sistema Nervioso Central Hereditarias/genética , Humanos , LinajeRESUMEN
Rett syndrome is an X-linked neurodevelopmental disorder that develops a profound intellectual and motor disability and affects 1 from 10â¯000 to 15â¯000 live female births. This disease is characterized by a period of apparently normal development until 6-18 months of age when motor and communication abilities regress which is caused by mutations occurred in the X-linked MECP2 gene, encoding the methyl-CpG binding protein 2. This research study reports a molecular analysis via an exhaustive gene sequencing which reveals an unusual novel double mutation (c.695â¯Gâ¯>â¯T; c.880Câ¯>â¯T) located in a highly conserved region in MECP2 gene affecting the transcription repression domain (TRD) of MeCP2 protein and leading for the first time to a severe phenotype of Rett syndrome. Moreover, a computational investigation of MECP2 mutations demonstrates that the novel mutation c.695â¯Gâ¯>â¯T is highly deleterious which affects the MeCP2 protein showing also an adverse impact on MECP2 gene expression and resulting in an affected folding and decreased stability of MECP2 structures. Thus, the altered TRD domain engenders a disrupted process of MECP2 functions. Therefore, this is the first study which highlights a novel double mutation among the transcription repression domain (TRD) of MeCP2 protein in Rett patient with a severe clinical phenotype in North Africa region.
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Análisis Mutacional de ADN/métodos , Predisposición Genética a la Enfermedad/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Proteína 2 de Unión a Metil-CpG/genética , Mutación/genética , Síndrome de Rett/genética , Preescolar , Represión Epigenética/genética , Femenino , Marcadores Genéticos/genética , Pruebas Genéticas/métodos , Humanos , Patología Molecular/métodos , Fenotipo , Dominios Proteicos/genética , Análisis de Secuencia de ADN/métodos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Status Dystonicus is a rare complication of dystonia. It is a life threatening disorder that needs urgent treatment.The aim of this study is to describe clinical features, management and follow up of children with Status Dystonicus. METHODS: - We conducted a retrospective study over an 8-year period including all patients diagnosed with Status Dystonicus. Clinical characteristics, etiologies and management were analyzed. RESULTS: - Ten patients were included. Main features of Status Dystonicus were a severe generalized dystonia with vegetative signs. Laryngeal spasm and swallowing disorders were observed in 4 cases. Several treatments such as Levodopa, Anticholinergics, Baclofen, Benzodiazepines and Neuroleptics were tried. Mechanical ventilation was required in 4 cases. Two patients died due to rhabdomyolysis and respiratory failure. Others returned to their pre-Status Dystonicus. CONCLUSION: - Status Dystonicus is a life threatening condition that needs an urgent management on an intensive care unit. In fact, patients with Status Dystonicus can develop respiratory failure and metabolic complications.On the basis of our experience, we delineated a therapeutic approach in which the patient with Status Dystonicus needs supportive care, specific therapy of dystonia and intravenous sedative treatment.
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3-Phosphoglycerate dehydrogenase (3-PGDH) deficiency is a rare autosomal recessive disorder of serine biosynthesis. It is typically characterized by congenital microcephaly, intractable seizures of infantile onset, and severe psychomotor retardation. Diagnosis is suspected on decreased l-serine levels in plasma and cerebrospinal fluid (CSF) and confirmed by genetic study. Early diagnosis in index cases allows supplementation in serine and prevention of fixed lesions. Prenatal diagnosis and genetic counseling allows prevention of secondary cases. We report on the two first unrelated Tunisian families with 3-PGDH deficiency confirmed by biochemical and genetic study. We discuss clinical, biochemical, imaging, electroencephalographic, and therapeutic aspects and review the literature.
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Errores Innatos del Metabolismo de los Aminoácidos/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Fosfoglicerato-Deshidrogenasa/deficiencia , Convulsiones/genética , Serina/biosíntesis , Errores Innatos del Metabolismo de los Aminoácidos/metabolismo , Preescolar , Femenino , Humanos , Discapacidad Intelectual/metabolismo , Masculino , Microcefalia/metabolismo , Fosfoglicerato-Deshidrogenasa/genética , Convulsiones/metabolismo , TúnezRESUMEN
BACKGROUND: Corpus callosum malformations (CCM) represent one of the most common congenital cerebral malformations with a prevalence of around one for 4000 births. There have been at least 230 reports in the literature concerning 1q43q44 deletions of varying sizes discovered using chromosomal microarrays. This disorder is distinguished by global developmental delay, seizures, hypotonia, corpus callosum defects, and significant craniofacial dysmorphism. In this study, we present a molecular cytogenetic analysis of 2 Tunisian patients with corpus callosum malformations. Patient 1 was a boy of 3 years old who presented psychomotor retardation, microcephaly, behavioral problems, interventricular septal defect, moderate pulmonary stenosis, hypospadias, and total CCA associated with delayed encephalic myelination. Patient 2 was a boy of 9 months. He presented a facial dysmorphia, a psychomotor retardation, an axial hypotonia, a quadri pyramidal syndrome, a micropenis, and HCC associated with decreased volume of the periventricular white matter. Both the array comparative genomic hybridization and fluorescence in situ hybridization techniques were used. RESULTS: Array CGH analysis reveals that patient 1 had the greater deletion size (11,7 Mb) at 1q43. The same region harbors a 2,7 Mb deletion in patient 2. Here, we notice that the larger the deletion, the more genes are likely to be involved, and the more severe the phenotype is likely to be. In both patients, the commonly deleted region includes six genes: PLD5, AKT3, ZNF238, HNRNPU, SDCCAG8 and CEP170. Based on the role of the ZNF238 gene in neuronal proliferation, migration, and cortex development, we hypothesized that the common deletion of ZNF238 in both patients seems to be the most responsible for corpus callosum malformations. Its absence may directly cause CCM. In addition, due to their high expression in the brain, PLD5 and FMN2 could modulate in the CCM phenotype. CONCLUSION: Our findings support and improve the complex genotype-phenotype correlations previously reported in the 1qter microdeletion syndrome and define more precisely the neurodevelopmental phenotypes associated with genetic alterations of several genes related to this pathology.
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BACKGROUND: Acute intermittent porphyria (AIP) is a rare metabolic disorder of heme biosynthesis characterized by enzymatic defect of porphobiligen desaminase with accumulation and increased excretion of porphyrins and their precursors. Clinical picture is characterized by attacks with a triad of abdominal pain, psychiatric disorder and neurological involvement (central and peripheral). Peripheral nervous system manifestations, often precipitated by porphyrinogenic medications are of poor outcome. AIM: We report a new cases A 13-year-old girl who presented several attacks of AIP and developed acute severe axonal motor neuropathy, three weeks after porphyrinogenic medications (Famotidin, Phenobarbital and Nifedipine). CONCLUSION: We stress on the importance of early diagnosis of AIP to prevent serious neurological complications often precipitated by medications and the efficiency of heme arginate treatment when administrated early during the attacks.
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Arginina/uso terapéutico , Hemo/uso terapéutico , Enfermedades del Sistema Nervioso Periférico/etiología , Porfirias/complicaciones , Porfirias/tratamiento farmacológico , Porfirinógenos/efectos adversos , Enfermedad Aguda , Adolescente , Arginina/administración & dosificación , Electromiografía , Famotidina/efectos adversos , Femenino , Hemo/administración & dosificación , Hemo Oxigenasa (Desciclizante) , Humanos , Nifedipino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Fenobarbital/efectos adversos , Factores de TiempoRESUMEN
Parkinsonism is a rare complication of encephalitis in childhood. Association to an isolated involvement of substantia nigra is exceptional. Mechanisms of nigral cells neurotropism remain hypothetic. We report on three children presenting with postencephalitic parkinsonism and selective involvement of substantia nigra, with literature review and we discuss pathogenic mechanisms.
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Encefalitis/complicaciones , Trastornos Parkinsonianos/etiología , Sustancia Negra/patología , Niño , Preescolar , Encefalitis/patología , Encefalitis/fisiopatología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Trastornos Parkinsonianos/patología , Trastornos Parkinsonianos/fisiopatologíaRESUMEN
Diagnosis criteria of stiff-person syndrome (SPS) include progressive, fluctuating muscular rigidity and spasms with normal neurological examination. The presence of unusual features such as prominent limb rigidity with segmental signs and contracture, evidence of brainstem dysfunction, profound autonomic disturbances, CSF pleiocytosis or MRI abnormalities in patients with SPS presentation allows to classify these patients as progressive encephalomyelitis with rigidity (PER). We report a 50 year-old woman suffering from severe painful spasms of abdominal wall and limb muscles. Neurological examination showed pyramidal signs. EMG disclosed continuous muscle activity with superimposed discharges. Treatment with high doses of diazepam and baclofen led to moderate improvement of generalised stiffness. However, the right arm became more rigid with oedema and vasomotor changes. Subsequently, bilateral nystagmus and internuclear opthalmplegia appeared. There was mild CSF pleiocytosis. Associated auto-immune thyroiditis was found with positive anti-microsome antibodies and decreased thyroid hormones. Search for profound neoplasm was negative. The patient had three subacute bouts then she improved with methylprednisolone. The initial clinical presentation mimicking a SPS with subsequent diffuse involvement of the central nervous system and a striking localisation of a severe rigidity to one arm allowed to suspect the diagnosis of PER. The relationship between SPS and PER remains unclear because of the rarity of these disorders. The observation reported in this paper gives evidence that both the disorders are probably two clinical presentations of the same pathogenic process.
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Encefalomielitis/complicaciones , Encefalomielitis/diagnóstico , Rigidez Muscular/diagnóstico , Rigidez Muscular/etiología , Síndrome de la Persona Rígida/diagnóstico , Antiinflamatorios/uso terapéutico , Baclofeno/uso terapéutico , Diagnóstico Diferencial , Diazepam/uso terapéutico , Quimioterapia Combinada , Electromiografía , Encefalomielitis/tratamiento farmacológico , Potenciales Evocados Somatosensoriales , Femenino , Humanos , Metilprednisolona/uso terapéutico , Persona de Mediana Edad , Relajantes Musculares Centrales/uso terapéutico , Rigidez Muscular/tratamiento farmacológico , Rigidez Muscular/patología , Rigidez Muscular/fisiopatologíaRESUMEN
OBJECTIVES: To report clinical, pathological and genetic findings in a Tunisian kindred with autosomal recessive juvenile parkinsonism (AR-JP) linked to parkin gene. BACKGROUND: AR-JP has been mapped to chromosome 6q and is caused by several mutations of the parkin gene (Park 2). Pathological features in AR-JP are characterized by neuronal loss in substantia nigra (SN) without Lewy bodies (LB). PATIENTS AND METHODS: Three affected siblings with juvenile Parkinson's disease were studied. Pathological examination of the brain was performed in one of them. Linkage studies and mutation analysis of the parkin gene were performed. RESULTS: Clinical picture was characterized by the association of rest tremor, bradykinesia and rigidity. Parkinsonian signs markedly improved with levodopa treatment in the three siblings. Dystonia was observed in one patient and diurnal fluctuations of parkinsonian signs in another one. Linkage analysis showed homozygous haplotypes in patients as compared to unaffected individuals and mutation analysis of the parkin gene revealed a homozygous two-base AG deletion in exon 2 (101-102). Pathological examination of the brain in one patient showed marked loss of pigmented neurons with extraneuronal free melanin in the lateral and medial parts of the SN associated to a slight spongiosis and astrocytic gliosis. In the locus coeruleus, there was also loss of pigmented neurons without gliosis. No LB or neurofibrillary tangles were found neither by traditional nor by histo-immunological stainings. CONCLUSION: This Tunisian kindred with AR-JP linked to a micro-deletion of the parkin gene shows clinical similarities with the previously reported Japanese and European families. Pathological features of this kindred are compared to what has been reported in AR-JP families linked to large exonic deletions of this gene.
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Ligasas/genética , Trastornos Parkinsonianos/genética , Trastornos Parkinsonianos/patología , Ubiquitina-Proteína Ligasas , Adulto , Encéfalo/patología , Salud de la Familia , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Linaje , TúnezRESUMEN
Lesch Nyhan syndrome (LNS) is an X-linked recessive disorder due to complete deficiency of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme. Defect of the enzymatic activity is related to mutations of the HPRT1 gene. The disorder severity is due to neurological features and renal complications. Up to now, more than 300 mutations have been reported. We report on a Tunisian child with a severe phenotype due to a novel identified complex mutation.
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Hipoxantina Fosforribosiltransferasa/genética , Síndrome de Lesch-Nyhan/genética , Mutación/genética , Niño , Humanos , Hipoxantina Fosforribosiltransferasa/deficiencia , Masculino , TúnezRESUMEN
Joubert syndrome is a clinically and genetically heterogeneous ciliopathy characterized by a typical cerebellar and brainstem malformation (the "molar tooth sign"), and variable multiorgan involvement. To date, 24 genes have been found mutated in Joubert syndrome, of which 13 also cause Meckel syndrome, a lethal ciliopathy with kidney, liver and skeletal involvement. Here we describe four patients with mild Joubert phenotypes who carry pathogenic mutations in either MKS1 or B9D1, two genes previously implicated only in Meckel syndrome.
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Enfermedades Cerebelosas/genética , Trastornos de la Motilidad Ciliar/genética , Encefalocele/genética , Anomalías del Ojo/genética , Enfermedades Renales Quísticas/genética , Mutación , Enfermedades Renales Poliquísticas/genética , Proteínas/genética , Retina/anomalías , Anomalías Múltiples , Adulto , Enfermedades Cerebelosas/patología , Cerebelo/anomalías , Niño , Preescolar , Trastornos de la Motilidad Ciliar/patología , Proteínas del Citoesqueleto , Encefalocele/patología , Anomalías del Ojo/patología , Femenino , Humanos , Enfermedades Renales Quísticas/patología , Imagen por Resonancia Magnética , Masculino , Enfermedades Renales Poliquísticas/patología , Retina/patología , Retinitis Pigmentosa , Índice de Severidad de la EnfermedadRESUMEN
OBJECTIVE: Mirror movements (MM) have been described in several pathological conditions. Their association with neural tube defects is rare, and only 5 cases have been reported in literature to date. We report on a case of MM associated with cervical myelomeningocele, and we discuss the diffusion tensor imaging findings and the underlying mechanism.
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Inborn errors of metabolism (IEM) are a group of genetic disorders characterized by dysfunction of an enzyme or other protein involved in cellular metabolism.(1) Most IEMs involve the nervous system (neuro-metabolic diseases or NMD). NMD often present with a complex clinical picture: psychomotor retardation and/or regression, pyramidal signs, ataxia, hypotonia and epilepsy and movement disorders.(1) Movement disorders are more frequently part of this complex picture than a predominant symptom, however in some instances the clinical picture may be summarized in an invalidating movement disorder.(2) On a phenomenology basis, one can distinguish eight main types of movement disorders: dystonia and athetosis, chorea, tremor with or without parkinsonism, ballismus, myoclonus, tics and stereotypies. Most of these abnormal involuntary movements generate from a dysfunction or a lesion in the basal ganglia, excepting myoclonus, the origin of which can vary (cortical, brainstem, basal ganglia, spinal and even peripheral nervous system).(3) Classically the most frequently observed movement disorders in NMD are: dystonia, myoclonus, chorea, tremor and parkinsonism (Fig. 1). The primary goal of this article is, departing from the literature and a large personal series, to describe the types of movement disorders most frequently observed in NMD and to discuss their clinical value in the setting of specific types of NMD.
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Errores Innatos del Metabolismo/complicaciones , Trastornos del Movimiento/etiología , Enfermedades del Sistema Nervioso/complicaciones , Humanos , Trastornos del Movimiento/clasificaciónRESUMEN
Mutations in the leucine-rich repeat kinase-2 gene (LRRK2) are responsible for some forms of familial as well as sporadic Parkinson's disease (PD). The purpose of this study was to examine the frequency of a single pathogenic mutation (6055G > A) in the kinase domain of this gene in United States and Tunisian familial PD and to compare clinical characteristics between patients with and without the mutation. Standardized case report forms were used for clinical and demographic data collection. We investigated the frequency of the most common substitution of LRRK2 (G2019S, 6055G>A) and its impact on epidemiological and phenotypic features. The frequency of mutations in Tunisian families was 42% (38/91) and in U.S. families 2.6% (1/39), with the unique opportunity to compare homozygous (n = 23) and heterozygous (n = 109) Tunisian carriers of G2019S substitutions. Individuals with G2019S substitutions had an older age at onset but few other differences compared with families negative for the substitution. Patients with LRRK2 mutations had typical clinical features of PD. Comparisons between individuals with heterozygous and homozygous LRRK2 mutations suggested that gene dosage was not correlated with phenotypic differences; however, the estimated penetrance was greater in homozygotes across all age groups.
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Salud de la Familia , Glicina/genética , Enfermedad de Parkinson/epidemiología , Enfermedad de Parkinson/genética , Proteínas Serina-Treonina Quinasas/genética , Serina/genética , Adulto , Anciano , Anciano de 80 o más Años , Comparación Transcultural , Análisis Mutacional de ADN , Femenino , Pruebas Genéticas/métodos , Genotipo , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Masculino , Persona de Mediana Edad , Mutación/genética , América del Norte/epidemiología , América del Norte/etnología , Túnez/epidemiología , Túnez/etnología , Población BlancaRESUMEN
We screened LRRK2 mutations in exon 41 in 904 parkin-negative Parkinson's disease (PD) patients (868 probands) from 18 countries across 5 continents. We found three heterozygous missense (novel I2012T, G2019S, and I2020T) mutations in LRRK2 exon 41. We identified 11 (1.3%) among 868 PD probands, including 2 sporadic cases and 8 (6.2%) of 130 autosomal dominant PD families. The LRRK2 mutations in exon 41 exhibited relatively common and worldwide distribution. Among the three mutations in exon 41, it has been reported that Caucasian patients with G2019S mutation have a single-founder effect. In the present study, Japanese patients with G2019S were unlikely to have a single founder from the Caucasian patients. In contrast, I2020T mutation has a single-founder effect in Japanese patients. Clinically, patients with LRRK2 mutations had typical idiopathic PD. Notably, several patients developed dementia and psychosis, and one with I2020T had low cardiac (123)I-metaiodobenzylguanidine (MIBG) heart/mediastinum ratio, although the ratio was not low in other patients with I2020T or G2019S. Clinical phenotypes including psychosis, dementia, and MIBG ratios are also heterogeneous, similar to neuropathology, in PD associated with LRRK2 mutations.