Diagnosis by whole exome sequencing of atypical infantile onset Alexander disease masquerading as a mitochondrial disorder

IntroductionThere are many similarities, both clinical and radiological, between mitochondrial leukoencephalopathies and Alexander disease, an astrogliopathy. Clinically, both can manifest with a myriad of symptoms and signs, arising from the neonatal period to adulthood. Radiologically, both can demonstrate white matter changes, signal abnormalities of basal ganglia or thalami, brainstem abnormalities and contrast enhancement of white matter structures. Magnetic resonance spectroscopy may reveal elevation of lactate in the abnormal white matter in Alexander disease making the distinction even more challenging.Patient and MethodsWe present a child who was considered to have an infantile onset mitochondrial disorder due to a combination of neurological symptoms and signs (developmental regression, failure to thrive, episodic deterioration, abnormal eye movements, pyramidal and cerebellar signs), urinary excretion of 3-methyl-glutaconic acid and imaging findings (extensive white matter changes and cerebellar atrophy) with a normal head circumference. Whole exome sequence analysis was performed.ResultsThe child was found to harbor the R416W mutation, one of the most prevalent mutations in the glial fibrillary acidic protein (GFAP) gene that causes Alexander disease.ConclusionsAlexander disease should be considered in the differential diagnosis of infantile leukoencephalopathy, even when no macrocephaly is present. Next generation sequencing is a useful aid in unraveling the molecular etiology of leukoencephalopathies.     

Differential diagnosis of cerebellar atrophy in childhood.

Starting from the imaging appearance of cerebellar atrophy (CA) we provide checklists for various groups of CA: hereditary CA, postnatally acquired CA, and unilateral CA. We also include a list of disorders with ataxia as symptom, but no evidence of CA on imaging. These checklists may be helpful in the evaluation of differential diagnosis and planning of additional investigations. However, the complete constellation of clinical (including history and neurological examination), imaging, and other information have to be considered. On the basis of a single study distinction between prenatal onset atrophy, postnatal onset atrophy, and cerebellar hypoplasia is not always possible. Apart from rare exceptions, neuroimaging findings of CA are nonspecific. A pattern-recognition approach is suggested, considering isolated (pure) CA, CA and hypomyelination, CA and progressive white matter abnormalities, CA and basal ganglia involvement, and cerebellar cortex hyperintensity.     

Shah-Waardenburg syndrome and PCWH associated with SOX10 mutations: a case report and review of the literature.

Shah-Waardenburg syndrome is a rare congenital disorder with variable clinical expression, characterised by aganglionosis of the rectosigmo?d (Hirschsprung disease), and abnormal melanocyte migration, resulting in pigmentary abnormalities and sensorineural deafness (Waardenburg syndrome). Mutations in the EDN, EDNRB and SOX10 genes can be found in patients with this syndrome. SOX10 mutations are specifically associated with a more severe phenotype called PCWH: peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease. Neuronal expression of SOX10 occurs in neural crest cells during early embryonic development and in glial cells of the peripheral and central nervous systems during late embryonic development and in adults. We present a 4-year-old girl with the PCWH phenotype associated with a de novo nonsense mutation (S384X) in SOX10. Main clinical features were mental retardation, peripheral neuropathy, deafness, Hirschsprung disease, distal arthrogryposis, white hairlock, and growth retardation. She presented with hypotonia, developmental delay, reduced peripheral nerve conduction velocities, and radiologically assessed central hypomyelination. Subsequently, the formation of abnormal myelin within the central and peripheral nervous system was functionally and radiologically assessed. Children presenting with features of Waardenburg syndrome and neurological dysfunction should be tested for mutations in the SOX10 gene to enable diagnosis and counselling.     

Marinesco-Sjögren syndrome due to SIL1 mutations with a comment on the clinical phenotype

BackgroundMarinesco-Sjögren syndrome is an autosomal recessive cerebellar ataxia, characterised by cerebellar ataxia, myopathy, cataracts and intellectual disability, due to mutations in the SIL1 gene.MethodsThe clinical features and two novel SIL1 mutations of four Dutch patients with Marinesco-Sjögren syndrome are described and compared to the literature on genetically proven Marinesco-Sjögren patients.ResultsThe core phenotype of this syndrome appears homogeneous, but: [1] cataract can develop later than the motor and cognitive signs; [2] myopathy is an early feature that seems progressive during the course of the disease; [3] serum creatine kinase is normal or only mildly elevated; [4] peripheral neuropathy is absent; and [5] a variable degree of intellectual disability is present in most Marinesco-Sjögren patients.ConclusionsBecause the late appearance of some hallmarks and the uncertainty as to whether incomplete phenotypes occur, SIL1 mutation analysis is helpful early in the diagnostic work-up of children with suspected inherited ataxias.     

Phenotypic and genotypic variability in Alpers syndrome

BackgroundAlpers syndrome is one of the most common phenotypes of mitochondrial disorders in early childhood and has been associated with pathogenic mutations in POLG1.AimsTo investigate the phenotypic–genotypic correlations in Alpers syndrome and to identify potential differences among patients with Alpers syndrome with or without pathogenic POLG1 mutations.MethodsPatients with the phenotype of Alpers syndrome who were referred to our pediatric hospital during 1984–2007 and were diagnosed with mitochondrial encephalomyopathy underwent further biochemical, morphological and genetic investigations.ResultsA total of 19 patients were included in the study, of whom six had pathogenic POLG1 mutations including a novel mutation (c.907 G > A, p.Gly303Arg). Complete mtDNA sequencing in the subgroup without POLG1 mutations showed 5 novel and 5 very rare mtDNA variants considered as rare polymorphisms. Compared to POLG1(?) patients, the POLG1(+) patients more frequently had seizures at onset, which often became refractory. Ataxia and stroke-like episodes were much more common, while microcephaly and spasticity were encountered almost solely in the POLG1(?) group. Hepatic and ophthalmological involvement developed in 79% and 88% of patients, respectively. Most of the patients in both groups had predominant deficiency of complex I. In addition to the major degenerative changes in the cerebral cortex, the basal ganglia, thalamus and white matter were also involved to variable extent.ConclusionAlpers syndrome is a heterogeneous syndrome that should be considered in patients with early-onset progressive cortical encephalopathy regardless of liver involvement. The phenotype is different depending on the presence or absence of POLG1 mutations.     

Ophthalmological abnormalities in children with cerebral white matter disorders.

The use of magnetic resonance imaging (MRI) in children with severe neurological impairment has defined a subgroup with increased T2-signals from cerebral white matter. The causes of white matter abnormalities are for the most part unknown, despite extensive investigation. Their clinical correlates and characteristics have still to be systematically analysed and described. We have compared clinical, ophthalmological and electro-ophthalmological findings in such children to delineate neurological and MRI patterns and have sought to correlate with the progression of disease. Clinical and electro-ophthalmological investigations were performed in 26 children with cerebral white matter abnormalities of unknown aetiology; 25 of the 26 children showed abnormalities, 23 clinical and 18 electro-ophthalmological. Optic nerve abnormalities, severe visual impairment and strabismus were the most common. Electro-ophthalmological abnormalities were increased latencies and abnormal waveform of the visual evoked potentials (VEP). Children with progressive disease all had abnormal VEP, whereas none of the ten children with a normal VEP deteriorated. We conclude that children with cerebral white matter abnormalities almost invariably had ophthalmological and often VEP abnormalities. Normal VEP was correlated with non-progressive disorder, as was hypoplasia or malformation of the papilla, whereas abnormal VEP were associated with progressive disease.     

Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation

ObjectiveTo describe the results obtained in a neonatal screening program after its implementation and to assess the clinical and molecular profiles of confirmed and suspicious congenital adrenal hyperplasia cases.MethodsA cross-sectional study was conducted. Newborns with suspected disease due to high 17-hydroxyprogesterone levels and adjusted for birth weight were selected. Classical congenital adrenal hyperplasia (salt-wasting and simple virilizing forms) was diagnosed by an increase in 17-hydroxyprogesterone levels as confirmed in the retest, clinical evaluation, and genotype determined by SNaPshot and multiplex ligation-dependent probe amplification.ResultsAfter 24 months, 15 classic congenital adrenal hyperplasia cases were diagnosed in a total of 217,965 newborns, with an estimated incidence of 1:14,531. From 132 patients, seven non-classical and 14 heterozygous patients were screened for CYP21A2 mutations, and 96 patients presented false positives with wild type CYP21A2. On retest, increased 17-hydroxyprogesterone levels were found in classical congenital adrenal hyperplasia patients and showed significant correlation with genotype-related classical genital adrenal hyperplasia. The most frequent mutations were IVS2-13A/C>G followed by gene deletion or rearrangement events in the classical form. In non-classical and heterozygous diseases, p.Val282Leu was the most common mutation.ConclusionsThe results underscore the effectiveness of congenital adrenal hyperplasia neonatal screening in the public health system and indicate that the adopted strategy was appropriate. The second sample collection along with genotyping of suspected cases helped to properly diagnose both severe and milder cases and delineate them from false positive patients.     

儿童幼年型粒单核细胞白血病突变基因型与临床特征分析

目的 探讨儿童幼年型粒单核细胞白血病(JMML)突变基因类型及其临床特征.方法 回顾性分析临床诊断明确且完成JMML 常见突变基因检测的14 例患儿临床资料.结果 14 例JMML 患儿中,男11 例(79%),女3 例(21%).诊断时中位年龄2.0 岁(范围0.6~6.0 岁).14 例患儿中检出PTPN11 基因突变4 例(29%),N-RAS 基因突变3 例(21%),1 例同时伴有PTPN11 和K-RAS 基因突变(7%),6 例未检测到突变基因(43%).4 例PTPN11 基因突变患儿均为男性,中位发病年龄2.5 岁,从发病至明确诊断中位时间为1.0 个月,外周血WBC 计数及单核细胞绝对值明显增高,PLT 计数降低,随访至今3 例患儿死亡,1 例病情进展;3 例N-RAS 基因突变患儿男女比例为2: 1,中位发病年龄2.0 岁,从发病至明确诊断中位时间13.7 个月,随访至今2 例患儿死亡,1 例未见明显进展.结论 PTPN11 是JMML 最常见的突变基因类型,常伴有血WBC计数及单核细胞绝对值增高,PLT 计数降低,疾病进展迅速,预后不良;N-RAS 突变病例病情进展缓慢;复合突变基因类型由于病例数少,临床特征有待于临床进一步观察.     

Le diabète insipide central chez l'enfant : étude de six observations

IntroductionThe central insipid diabetes (DIC) is defined by the excretion — abnormally important — of dilute urines at an absolute or relative deficiency in endogen vasopressin and susceptible to exogen vasopressin.Patients and methodsThe authors have studied retrospectively 6 cases of DIC hospitalised in the CHU Hédi Chaker of Sfax pediatrics service over a period of 19 years starting from the 1st of January 1987 though the 31st of December 2005. They have studied in our patients the clinic, biologic, neuroradiologic and etiologic particularities.ResultsDuring the period of study, the authors have studied 6 cases of DIC. The average age was of 7 years (1 year 9 months–13 years 3 months). The polyuropolydipsic syndrome represented the reason of consultation of all our patients. Hypotonic polyurie was constant with all children, it was about an average of 12,2 ml/kg/h. The test of hydrous restriction coupled with the Minirin^® test has allowed us to perform the diagnosis of the DIC in all cases. The etiologic analyses including a neuroradiologic imagery (IRM and/or cerebral scanner) has permitted to show an expansive process of the median line (germinome) with one patient, an growth of the pituitary stem one patient, the cerebral scanner has been done to 2 children and it was normal. A patient was lost before doing the imagery. The thoracic scanner realized for one patient presenting dyspnoea showed pulmonary emphysema with an interstitial syndrome in aid of a langherancienne histiocytose. The coetaneous biopsy made on another patient having presented cuteness lesions confirmed too the diagnosis of Histiocytose. The DIC is idiopathic with the two other patients. The evolution has been marked by the death in one case, a progressive aggravation dyspnoea with 1 patient; otherwise, it was favourable for the other patients.ConclusionThe DIC is rare in the child, the historic clinic brutal making the diagnostic easy; it is not the case with the investigations permitting to discover an etiology that can unmask over a long period justifying a prolonged supervision.     

Osteopetrosis mimicking juvenile myelomonocytic leukemia

A 5‐month‐old boy developed splenomegaly, anemia, thrombocytopenia with elevated white cells, monocytosis and immature granulocytes in the peripheral blood. Bone marrow showed dysplasia without blastosis. Increased colony‐forming unit‐granulocyte–macrophage was found in the peripheral blood, mimicking granulocyte–macrophage colony‐stimulating factor hypersensitivity. These findings fulfilled the diagnosis criteria for juvenile myelomonocytic leukemia (JMML), but no mutations in the CBL, NRAS, KRAS, or PTPN11 genes were detected. In addition to these findings severe hypogammaglobulinemia and elevated alkaline phosphatase were present. Bone X‐ray showed dense and radiopaque bones with a bone‐in‐bone appearance characteristic of infantile malignant osteopetrosis (IMO). Genetic mutation in T‐cell, immune regulator 1 (TCIRG1) was identified, confirming the diagnosis of IMO. Careful differential diagnosis including osteopetrosis, is therefore recommended in patients with clinical features and hematologic findings consistent with JMML.     

Tripeptidyl peptidase 1 in patients with late infantile neuronal ceroid lipofuscinosis

IntroductionNeuronal ceroid lipofuscinoses are a group of inherited autosomal recessive lysosomal diseases, most commonly found in infancy. These are neuropathologically characterised by accumulation of an autofluorescent lipopigment in neurons and other cells. This condition is clinically characterised by loss of motor and cognitive skills, lack of motor coordination, ataxia, progressive visual impairment, behavioural changes; seizures of difficult to manage seizures, particularly myoclonic, and premature death. Ten clinical forms have been described, one of which is late infantile where clinical signs begin between two and four years. The gene responsible for this disease is located at 11p15 locus, and the enzyme encoded by this gene is the tripeptidyl peptidase 1.Patients and methodsWe standardised the technique for the enzymatic diagnosis of late infantile neuronal ceroid lipofuscinoses from dried blood on filter paper card in 76 healthy individuals adults and children in order to establish a normal range in the Venezuelan population. The tripeptidyl peptidase activity was also determined in 9 patients with a clinical diagnosis of late infantile neuronal ceroid lipofuscinoses.ResultsSix of the samples showed activity lower than the lowest control value (0.11 to 0.45 nmol/spot) from healthy controls of infantile age, confirming the enzymatic diagnosis. Three of the 14 parent samples analysed showed values in the heterozygote ranges.ConclusionsThe enzymatic diagnosis of late infantile neuronal ceroid lipofuscinoses from dried blood on filter paper card is a rapid, easier, less expensive and accurate molecular diagnosis tool.     

异染性脑白质营养不良的临床及实验室研究

评价异染性脑白质营养不良（MLD）的临床特征和白细胞芳基硫酸酯酶A（ASA）的诊断价值。方法对本院确诊6例MLD患儿临床与实验室检测资科进行分析。结果晚期婴儿型5例,发病年龄1～2．5a,少年型1例6a起病。患儿病前智力发育正常。起病表现均为步态异常,且进行性加重至双下肢或四肢呈痉挛性瘫痪,出现语言及智力倒退各3例。脑CT检查3例示双侧半球对称性低密度影,MRI5例示双侧大脑白质对称性长T1、长T2信号影。6例白细胞ASA活性缺乏或低下。结论进行性运动障碍,语言障碍及智力倒退为本病主要临床特征。CT／MRI脑白质的异常改变有助于诊断。确诊依据白细胞ASA活性减低。     

Pelizaeus-Merzbacher disease: the diagnostic contribution of MRI

Pelizaeus-Merzbacher disease is a rare sex-linked leukodystrophy. Its metabolic basis has not been identified yet and diagnosis in mainly based on clinical findings and pathological investigation. Cerebral biopsy is not always performed because of lack of available therapy. Genetic counseling can be provided if the diagnosis is secured. Four cases are reported, in children with characteristic signs, who underwent magnetic resonance (MR) Imaging. MR Imaging appears to be more sensitive than computed tomography to visualize white matter disease: T1 weighted images suggest hypomyelination, in conformity with abnormal myelination. T2 weighted images show a non specific high signal in the white matter.     

Evolución clínica de la forma hiperaguda de la encefalomielitis aguda desmielinizante

IntroductionAcute disseminated encephalomyelitis (ADEM) is an inflammatory disease that damages the white matter of the central nervous system. Its clinical course is monophasic and multifocal. The outcome is usually favourable. We report our experience in the management of the hyperacute form of ADEM.Patients and methodsA retrospective chart review was performed on five patients admitted in coma with a diagnosis of ADEM in the Paediatric Intensive Care Unit (PICU). We describe their epidemiological, clinical, microbiological, magnetic resonance imaging features and their treatment and outcomes.ResultsThe mean age was 5.2 years and all were male. None of them fulfilled radiologic criteria for acute haemorrhagic leukoencephalitis. At admission all patients were in a coma, and all were on controlled mechanical ventilation support. Before their admission all patients had fever. In all cases the time between the first neurological symptom and coma was ≤ 24 hours. The cerebrospinal fluid examination was abnormal in three patients, and in one case, oligoclonal bands were detected. The first brain magnetic resonance imaging (MRI) showed white matter and basal ganglia lesions in all patients, and in three cases the spinal medulla was affected by demyelination. All patients were treated with a course of high-dose methylprednisolone. Four patients were also treated with high-dose immunoglobulins, and one of them received plasmapheresis. Two patients died, and one patient had severe sequelae at discharge from the PICU. At discharge the lesions in the white matter were still present in the MRI. After nine months the three survivors had a Glasgow Outcome Scale score of five and no one relapsed.ConclusionsThere is a hyperacute clinical form of ADEM which has a high mortality rate. In the short term, the clinical improvement of hyperacute ADEM is not accompanied by a decrease of severity of the brain MRI.     

Retrospective study of 75 children with peripheral inherited neuropathy: Genotype–phenotype correlations

Introduction

Charcot-Marie-Tooth disease (CMT) is an inherited peripheral neuropathy with an impact on patients’ quality of life and wide genetic heterogeneity. Next-generation sequencing (NGS) has extended the molecular diagnosis. This study aims to describe a cohort of patients with CMT onset in childhood to explore genotype–phenotype correlations.

Clinical Studies of Patients with Rubella Syndrome Occurring in a High Incidence in the Ryukyu Islands in 1965: On the Diagnostic Significance of Clinical Manifestations

The 620 cases with a history of maternal rubella and/or with one or more of cataract, CHD and deafness born in the Ryukyu Islands in 1965 were subjected to clinical studies and 360 cases were diagnosed as rubella syndrome. Rubella retinopathy makes a reliable diagnostic basis for rubella syndrome. As for the typical combination of clinical manifestations, the cases with cataract have CHD, deafness and retinopathy; the cases with CHD not accompanied by cataract have deafness and retinopathy; and the cases with deafness not accompanied by cataract and CHD either have or have not retinopathy. The cases with cataract alone or with CHD can extremely rarely be denned as having rubella syndrome. There existed the close relationship between the combination of clinical manifestations and the time of maternal rubella infection. The main clinical manifestations of rubella syndrome are cataract, congenital heart disease (CHD), and deafness appearing singly or two or more together¹⁾²⁾. Etiology of the congenital cataract, CHD, or deafness is mostly not explained; and only a small portion of the incidence is due to intrauterine rubella infection. For the future of the patients in the above conditions and for their parents, clarification as to whether they are or are not due to rubella is very important. Current general practice for the diagnosis of rubella syndrome is laboratory diagnosis that measures rubella hemagglutination inhibition (HI) antibodies³⁾⁴⁾. As the infants grows in age, the above mentioned technique may not assure an absolute judgment⁵⁾⁶⁾. This makes it necessary to arrive at diagnosis from the clinical findings. A prompt, direct diagnosis from the clinical findings alone will be very convenient. In the Ryukyu Islands where there was a high incidence of rubella syndrome in infants in the second half of 1965, we analyzed clinical findings of the affected children with cataract, CHD or deafness on the basis of serological diagnosis. The diagnostic significance of the clinical findings was so studied. Hence our report in this paper.     

Pyruvate dehydrogenase E2 deficiency: A potentially treatable cause of episodic dystonia

The association of progressive episodic dystonia and learning disability with distinctive neuroimaging findings may lead to consideration of atypical Pantothenate Kinase Associated Neurodegeneration (PKAN) and investigations directed towards that diagnosis. Recent reports indicate that deficiency of dihydrolipoamide acetyltransferase, the E2 component of the pyruvate dehydrogenase complex, may present similarly, and that this disorder should also be considered in the differential diagnosis. We describe two sisters with early onset episodic dystonia and pyruvate dehydrogenase deficiency caused by defects in the E2 subunit. Both have neuroimaging features similar to previously described patients and have mutations in the DLAT gene. As this condition is potentially treatable with a ketogenic diet, the possibility of this diagnosis should be considered in similar cases.     

肾上腺脑白质营养不良23例临床与实验室分析

目的深化对肾上腺脑白质营养不良(ALD)的认识。方法分析1987~2005年确诊为ALD的23例患者的临床和实验室资料。结果23例ALD患者均为男性;起病年龄0~18.5岁;均有中枢神经系统和内分泌系统受累的表现。神经系统变化包括行为、认知异常和神经系统的阳性体征;内分泌系统表现包括肾上腺皮质功能的进行性减退和生长发育迟缓。其中10例患者有阳性家族史;22例有颅脑CT和MRI的特征性表现,以枕叶、顶叶、侧脑室、颞叶为主;14/15例患者有原发性肾上腺皮质功能减低。结论诊断ALD须结合家族史、临床特点、特异生化检查、神经影像学检查。推荐对ALD疑似病例首先进行皮质醇、ACTH实验及颅脑MRI检查。     

Congenital hydrocephalus: Nosology and guidelines for clinical approach and genetic counselling

Congenital hydrocephalus is a serious condition that can arise from multiple causes. It comprises a diverse group of conditions which result in impaired circulation and absorption of cerebrospinal fluid. Congenital malformations of the central nervous system, infections, haemorrhage, trauma, teratogens and, occasionally, tumours can all give rise to hydrocephalus. In this paper we focus on the genetic aspects of hydrocephalus, excluding neural tube defects. The incidence is 0.4–0.8 per 1000 liveborns and stillbirths. X-linked hydrocephalus comprises approximately 5% of all cases. This condition is caused by mutations in the gene at Xq28 encoding for L1, a neural cell adhesion molecule. Carrier detection and prenatal diagnosis can be offered to affected families by means of chorionic villus biopsy and linkage analysis or L1 mutation analysis. In general, recurrence risk for congenital hydrocephalus excluding X-linked hydrocephalus, is low; empiric risk figures found in various studies range from <1% to 4%. Unfortunately, prenatal diagnosis based on an early ultrasound scan is not always reliable as ventriculomegaly usually starts after 20 weeks of gestation. We stress the importance of additional clinical investigations. Prognosis in the prenatally diagnosed patients depends on additional malformations but in general, is not very good. Conclusion Congenital hydrocephalus may be non-syndromic and syndromic. Prognosis depends primarily on the underlying cause and/or associated malformations, which have to be delineated on the basis of clinical, cytogenetic and molecular analysis. Received: 5 June 1997 / Accepted in revised form: 21 November 1997     

Cerebral white matter disease in children may be caused by mitochondrial respiratory chain deficiency

Several mitochondrial diseases are known to occasionally involve the cerebral white matter, namely Leigh syndrome, Kearns-Sayre syndrome, and MELAS syndrome, but in these cases the major finding is alteration in the basal ganglia and brainstem. Here we report on severe diffuse white matter involvement and respiratory chain enzyme deficiency or mitochondrial DNA rearrangement in 5 unrelated families. It is interesting that white matter lesions were the only abnormal neuroradiologic feature in 3 of the 5 families, and multiple small cyst-like white matter lesions were found in 2 of 5 probands. Respiratory chain deficiency should be considered in the diagnosis of severe white matter involvement in childhood.