Fetal hydrops in GM(1) gangliosidosis: a case report

GM(1) gangliosidosis is a rare disorder characterized by deficiency of the ss-galactosidase enzyme, with the resulting accumulation of glycolipids, oligosaccharides and especially GM(1) ganglioside. It can be classified into three clinical types according to the time of onset: infantile, juvenile and adult form. We report a case of GM(1) gangliosidosis presenting with fetal hydrops at 24 wk of gestation. The parents were consanguineous; the baby, born at 35 wk of gestation, was dysmorphic and presented severe generalized oedema. The most common cause of fetal hydrops was excluded. A lysosomal storage disease was suspected, and GM(1) gangliosidosis was diagnosed. The child developed severe growth and mental retardation and died when she was 21 mo old. CONCLUSION: We suggest that the possible association between inborn errors of metabolism and antenatal ascites should be considered, in order to offer genetic counselling due to the high recurrence risk and the availability of early antenatal diagnosis.     

Proton MRS of a child with Sandhoff disease reveals elevated brain hexosamine.

Sandhoff disease (gangliosidosis type 0) is a lysosomal storage disorder with a deficiency of hexosaminidases A and B. After an initially normal development the clinical course of affected children is severe and rapidly progressive leading to spastic tetraparesis, epileptic seizures and early death. In a 10-month-old girl with enzymatically established diagnosis of Sandhoff disease MRI of the brain showed signal changes in the periventricular white matter, pyramidal tract, basal ganglia, and cerebellar hemispheres. Proton MR spectroscopy (MRS) at the age of 13 months revealed a reduction of total N-acetylaspartate (neuroaxonal marker) as well as strongly elevated inositol (glial marker) in white matter, gray matter, and basal ganglia. A new resonance at 2.07 ppm was detected in all regions and ascribed to N-acetylhexosamine with highest concentrations in white matter and thalamus. While conventional MRS findings are in line with neuroaxaonal damage and pronounced astrocytosis, the observation of N-acetylhexosamine appears as a specific marker of Sandhoff disease indicating accumulation of hexosamine-containing oligosaccharides. This interpretation is supported by a recent in vitro MRS study of a Sandhoff mouse model. In conclusion, proton MRS of cerebral metabolites offers specific insights into the pathopysiologic processes of children with Sandhoff disease and may prove to represent another disease specific MRS pattern of the brain.     

Diagnosis of unsuspected fetal metabolic storage disease by routine placental examination

GM1 gangliosidosis (type 1) is a rare hereditary, autosomal recessive, lysosomal storage disease characterized by a marked deficiency of active acid beta-galactosidase resulting in accumulation of gangliosides and mucopolysaccharides in tissues. Disease status of newborns from affected kindreds may be diagnosed by placental examination. Typical findings include a characteristic vacuolar distension of the cytoplasm of syncytiotrophoblast and stromal Hofbauer cells. We report a case of unsuspected fetal storage disorder initially diagnosed by routine placental examination of a normal-appearing infant born to a previously unaffected family. Progressive, third-trimester oligohydramnios and fetal growth retardation had been documented by ultrasonography. Placental findings included vacuolization of syncytiotrophoblast, intermediate trophoblast, and stromal Hofbauer cells. Subsequent enzyme analysis confirmed the placental findings of storage disorder and diagnosed GM1 gangliosidosis.     

GM1 gangliosidosis and dilated cardiomyopathy

We report a child with a rare cardiac involvement in GM1 gangliosidosis. At the age of 9 months a secondary dilatative cardiomyopathy due to the metabolic disorder was diagnosed. During 2 years the functional echocardiographic signs became normal, though the ECG still was not normal. Our report is the first longterm observation and investigation of cardiac involvement in GM1 gangliosidosis.     

Diagnosis of Unsuspected Fetal Metabolic Storage Disease by Routine Placental Examination

GM1 gangliosidosis (type 1) is a rare hereditary, autosomal recessive, lysosomal storage disease characterized by a marked deficiency of active acid β-galactosidase resulting in accumulation of gangliosides and mucopolysaccharides in tissues. Disease status of newborns from affected kindreds may be diagnosed by placental examination. Typical findings include a characteristic vacuolar distension of the cytoplasm of syncytiotrophoblast and stromal Hofbauer cells. We report a case of unsuspected fetal storage disorder initially diagnosed by routine placental examination of a normal-appearing infant born to a previously unaffected family. Progressive, third-trimester oligohydramnios and fetal growth retardation had been documented by ultrasonography. Placental findings included vacuolization of syncytiotrophoblast, intermediate trophoblast, and stromal Hofbauer cells. Subsequent enzyme analysis confirmed the placental findings of storage disorder and diagnosed GM1 gangliosidosis.     

Congenital ascites as a presenting sign of lysosomal storage disease

Neonatal ascites is usually attributed to hematologic, genitourinary, gastrointestinal tract, or congenital heart disease. When these lesions have been excluded, metabolic storage disorders should be considered in the differential diagnosis. We report eight cases of neonatal ascites associated with different types of lysosomal storage disease: infantile sialidosis, Salla disease, GM1 gangliosidosis, and Gaucher disease. In each case there was a history of sibling of perinatal death resulting from the disease. In three cases the diagnosis of ascites was made in utero by ultrasound examination. These diseases are characterized by excretion in the fetal urine of abnormal catabolic products or by measurement of decreased activity of specific lysosomal hydrolases in cultured amniocytes. Thin-layer chromatography of the oligosaccharides in amniotic fluid may be indicated when a diagnosis of persistent fetal ascites has been established.     

核磁共振和核磁共振波谱结合粗大运动评定量表在儿童脑性瘫痪分度诊断的应用

目的 探讨头部核磁共振、核磁共振波谱以及粗大运动评定量表对儿童脑性瘫痪的分级诊断价值.方法 40例1.0～2.0周岁的健康儿童和42例1.1 ～2.0周岁的脑性瘫痪儿童为研究对象,对比正常儿童与脑性瘫痪患儿的MRI、MRS检测结果;根据核磁共振结果对脑性瘫痪进行分度,并用核磁共振波谱检测不同核磁共振分度的脑性瘫痪患儿脑内的NAA/Cr、CHO/Cr、LAC/Cr水平并分度;考察不同核磁共振和核磁共振波谱分度脑性瘫痪患儿的粗大运动评定量表得分情况.结果 核磁共振和核磁共振波谱均能有效区分脑性瘫痪患儿脑内的典型病变,脑内的NAA、Cr、Cho能被核磁共振波谱定量检测.不同核磁共振分度的患者脑内的NAA/Cr、CHO/Cr、LAC/Cr有所差异,重度患者与中度患者间的差异具有统计学意义(P＜0.05).脑性瘫痪的核磁共振波谱分度与核磁共振分度相符率不理想,但粗大运动评定量表评分表明各不同分度之间有差异(P＜0.05).结论 核磁共振和核磁共振波谱结合粗大运动评定量表可有效完善脑性瘫痪的分度诊断,这对不同类型儿童脑性瘫痪的临床治疗具有一定的指导意义.     

Lafora disease: Spectroscopy study correlated with neuropsychological findings

PURPOSE: To evaluate the metabolic changes both in grey and white matter in Lafora disease using proton magnetic resonance spectroscopy and to determine the possible correlation with the pattern of cognitive impairment. METHODS: Five patients with Lafora disease and six healthy controls were included in the study. Patients underwent at the same time-point neuropsychological testing and 1[H]MRS, using PRESS sequences (TE=136 and 25 ms) positioned in the frontal and posterior cingulate gyrus cortexes and in the adjacent frontal and parietal white matter. RESULTS: Neuropsychological testing showed in all patients a prevalent involvement of performance abilities--with partial sparing of verbal competences--and of executive functions, suggesting a major involvement of frontal areas. Analysis of 1[H]MRS showed a statistically significant reduction in NAA/mI and NAA/Cr in grey matter of patients compared to controls, more significant in frontal regions. In white matter, a significant reduction of NAA/mI ratio was observed both in the frontal and parietal regions, associated with a reduction of the NAA/Cr only in the frontal white matter. NAA/mI was found to be the most statistically significant altered parameter in all regions studied and the only significantly altered ratio in strong correlation with all sets of neuropsychological parameters. CONCLUSIONS: Our study confirmed the predominant metabolic damage in the frontal cortex, also demonstrating NAA/mI ratio to be the most sensitive parameter to detect metabolic brain changes in Lafora disease; moreover, it evidenced frontal white matter spectroscopic changes. Both spectroscopy values and clinical features of cognitive impairment showed a prevalent frontal impairment.     

Serial 1H-MRS in GM2 gangliosidoses

GM2 gangliosidoses are a group of neuronal storage disorders caused by deficiency in the lysosomal enzyme hexosaminidase A. Clinically, the disease is marked by a relentless encephalopathy. Proton magnetic resonance spectroscopy (1H-MRS) provides in-vivo measurement of various brain metabolites including N-acetyl aspartate+N-acetyl aspartate glutamate (NAA), myo-inositol (mI), choline (Cho) and creatine (Cr). The NAA represents neuronal integrity while elevation in the mI reflects abnormal inflammation and gliosis in the brain tissue. An elevation in the Cho levels suggest cell membrane breakdown and demyelination. We report the clinical and laboratory data in two patients with GM2 gangliosidoses. Serial 1H-MRS evaluations were performed to drive metabolite ratios of NAA/Cr, mI/Cr and Cho/Cr. We acquired the data from four regions of interest (ROI) according to a standard protocol. The results documented a progressive elevation in mI/Cr in all four ROI in patient one and only one ROI (occipital gray matter) in patient 2. We also documented a decline in the NAA/Cr ratios in both cases in most ROI. These results were compared to six age-matched controls and confirmed statistically significant elevation in the mI in our cases. In conclusion, 1H-MRS alterations were suggestive of neuronal loss and inflammation in these patients. 1H-MRS may be a valuable tool in monitoring the disease progress and response to therapy in GM2 gangliosidoses. Elevation in the mI may prove to be more sensitive than the other metabolite alterations.     

Proton magnetic resonance spectroscopy: normal findings in the cerebellar hemisphere in childhood

BACKGROUND: The cerebellar hemispheres (CER) are different from the supratentorial white and gray matter embryologically, in cytoarchitecture, and probably in metabolic activity. Proton magnetic resonance spectroscopy ((1)H MRS) can provide a noninvasive biochemical analysis of this region. OBJECTIVE: To study, with (1)H MRS, metabolite concentrations in CER as a function of age and compare these metabolic data with those of parietoccipital white matter (PO WM) in healthy children. MATERIALS AND METHODS: Using single-voxel (1)H MRS, we studied 37 volunteers (3-18 years) with normal MRI scans of the brain. (1)H MRS was performed using the PRESS technique in CER and PO WM. The NAA/Cr, Cho/Cr, NAA/H(2)O, Cr/H(2)O, and Cho/H(2)O ratios were analyzed as a function of age. Metabolic data from these regions were compared. RESULTS: The NAA/Cr ratio tended to increase with age in CER. Mean NAA/Cr and Cho/Cr ratios were found to be lower in CER than in PO WM. Mean NAA/H(2)O, Cr/H(2)O, and Cho/H(2)O ratios in CER were higher than in the PO WM. CONCLUSION: Our data confirm the regional variations between CER and PO WM metabolite ratios, and demonstrate a tendency of age-dependent change of the NAA/Cr ratio in CER. The creatine concentration was significantly higher in the cerebellum than in the PO WM.     

磁共振波谱测定癫痫患儿脑内代谢变化及其临床意义的研究

目的 了解癫痫患儿脑内代谢变化的特点。方法 应用Ｅｌｓｃｉｎｔ２．０Ｔ超导型太共振仪,对２５例癫痫、５例难治性癫痫患儿脑内Ｎ－乙酰天门冬氨酸（ＮＡＡ）、肌酸和磷酸肌酸（Ｃｒ）、及含胆碱化合物（Ｃｈｏ）的浓度进行测定,并以１０例非颅内疾病患儿作为对照。结果 癫痫组致二内ＮＡＡ及ＮＡＡ／（Ｃｒ＋Ｃｈｏ）比值明显低于病灶对侧（Ｐ〈０．０１）,难治性癫痫病程越长,临床发作次数越频繁,ＮＡＡ／（Ｃｒ＋Ｃｈｏ     

Sequential magnetic resonance spectroscopic changes in a patient with nonketotic hyperglycinemia

Nonketotic hyperglycinemia (NKH) is a rare inborn error of amino acid metabolism. A defect in the glycine cleavage enzyme system results in highly elevated concentrations of glycine in the plasma, urine, cerebrospinal fluid, and brain, resulting in glycine-induced encephalopathy and neuropathy. The prevalence of NKH in Korea is very low, and no reports of surviving patients are available, given the scarcity and poor prognosis of this disease. In the current study, we present a patient with NKH diagnosed on the basis of clinical features, biochemical profiles, and genetic analysis. Magnetic resonance spectroscopy (MRS) allowed the measurement of absolute glycine concentrations in different parts of the brain that showed a significantly increased glycine peak, consolidating the diagnosis of NKH. In additional, serial MRS follow-up showed changes in the glycine/creatinine ratios in different parts of the brain. In conclusion, MRS is an effective, noninvasive diagnostic tool for NKH that can be used to distinguish this disease from other glycine metabolism disorders. It may also be useful for monitoring NKH treatment.     

Magnetic resonance spectroscopy in pediatric neuroradiology: clinical and research applications

Magnetic resonance spectroscopy (MRS) offers a unique, noninvasive approach to assess pediatric neurological abnormalities at microscopic levels by quantifying cellular metabolites. The most widely available MRS method, proton (¹H; hydrogen) spectroscopy, is FDA approved for general use and can be ordered by clinicians for pediatric neuroimaging studies if indicated. There are a multitude of both acquisition and post-processing methods that can be used in the implementation of MR spectroscopy. MRS in pediatric neuroimaging is challenging to interpret because of dramatic normal developmental changes that occur in metabolites, particularly in the first year of life. Still, MRS has been proven to provide additional clinically relevant information for several pediatric neurological disease processes such as brain tumors, infectious processes, white matter disorders, and neonatal injury. MRS can also be used as a powerful quantitative research tool. In this article, specific research applications using MRS will be demonstrated in relation to neonatal brain injury and pediatric brain tumor imaging.     

孤独症谱系障碍儿童丘脑和小脑磁共振波谱特征和临床关系的前瞻性研究

目的 探究孤独症谱系障碍（autism spectrum disorder,ASD）儿童丘脑和小脑生化代谢物指标变化及与临床特征的关系。 方法 前瞻性采用磁共振波谱（magnetic resonance spectroscopy,MRS）单体素点分辨率波谱序列对50名2~6岁的ASD儿童双侧丘脑和小脑进行分析,以肌酸（creatine,Cr）为内标测定代谢物N-乙酰天冬氨酸（N-acetylaspartate,NAA）/Cr、胆碱（cholin,Cho）/Cr、肌醇（myoinositol,MI）/Cr、谷氨酸复合物（glutamine and glutamate complex,Glx）/Cr的相对值,比较各代谢物的差异和临床症状之间的关系。 结果 ASD儿童左侧丘脑NAA/Cr与Griffiths发育评估量表中文版中听力-语言和手眼协调评分呈正相关（P<0.05）;右侧小脑Cho/Cr与个人-社交、听力-语言、手眼协调呈正相关（P<0.05）;左侧丘脑和左侧小脑的NAA/Cr呈正相关,左侧丘脑和左侧小脑的Glx/Cr呈正相关（P<0.05）。ASD儿童丘脑和小脑部位左右两侧代谢物之间相比差异无统计意义（P>0.05）。 结论 ASD儿童小脑、丘脑存在代谢紊乱,且左侧小脑和左侧丘脑代谢物改变之间存在关联,部分指标与ASD临床症状相关。MRS可能揭示了ASD的病理基础并为其诊断、预后评估提供无创、定量检测方法。     

A child with macrocephaly: case report of a patient with megalencephalic leukoencephalopathy with subcortical cysts and a compound heterozygosity for two mutations in the MLC1 gene

Megalencephaly is as a rule accompanied by macrocephaly, an occipitofrontal circumference (OFC) greater than the 98th percentile. Megalencephaly is divided into an anatomic type (developmental) and a metabolic type. Metabolic megalencephaly refers to various storage and degenerative encephalopathies. The differential diagnosis includes Alexander's disease, Canavan's disease, glutaric aciduria type 1, GM1 and GM2 gangliosidosis, merosin-deficient variant of congenital muscular dystrophy and megalencephalic leukoencephalopathy with subcortical cysts (MLC). The distinctive features of this syndrome are enlarged cranial circumference, present at birth or starting in the first year of life, and magnetic resonance imaging (MRI) evidence of diffuse with matter abnormalities with subcortical cysts in the tips of the temporal lobes and in frontoparietal subcortical areas. Mutations in the MLC1 gene have been found as causative of MLC in 60-70 % of affected subjects, without genotype-phenotype correlation. The child we describe presented with progressive macrocephaly not associated with dysmorphic features and large abdominoscrotal hydrocele. At the age of 8 months, encephalic MRI showed anomalies suggestive for MLC and brainstem auditory evoked potentials (BAEP) documented alterations of signal conduction in right tracts. At the time, clinical neurologic examination was normal. Extensive metabolic assays were within normal range. Sequence analysis for MLC1 gene revealed a compound heterozygosity for two mutations in MLC1 gene, inherited from healthy non consanguineous parents.     

Prenatal diagnosis of GM2 gangliosidosis with high residual hexosaminidase A activity (variant B1; pseudo AB variant)

A case of infantile GM2 gangliosidosis with high residual beta-hexosaminidase A activity toward the synthetic substrate 4-methylumbelliferyl-2-acetamido-2-deoxy-beta-D-glucopyranoside was diagnosed prenatally. Extracts from cultured amniotic fluid cells of the fetus had a hexosaminidase A activity of 27% of total hexosaminidase but were almost completely unable to degrade [3H]ganglioside GM2 (less than 0.5% of control values) when assayed in the presence of the natural activator protein. These results were confirmed by analyses of fetal muscle fibroblasts, liver, and brain. All tissues examined showed a profound deficiency of ganglioside GM2 galactosaminidase despite hexosaminidase A levels in the heterozygote range. In brain tissue, ganglioside GM2 content was elevated more than 4-fold. Hydrolysis of p-nitrophenyl glucosaminide-6-sulfate, a substrate specific for hexosaminidases A and S, by tissue extracts was also markedly reduced but the residual activities found (5% in liver, 12% in fibroblasts, and 16% in brain) were much higher than those with the physiological lipid substrate, ganglioside GM2.     

Early increases in brain myo-inositol measured by proton magnetic resonance spectroscopy in term infants with neonatal encephalopathy.

Our aim was to assess brain myo-inositol/creatine plus phosphocreatine (Cr) in the first week in term infants with neonatal encephalopathy using localized short echo time proton magnetic resonance spectroscopy and to relate this to measures of brain injury, specifically lactate/Cr in the first week, basal ganglia changes on magnetic resonance imaging (MRI), and neurodevelopmental outcome at 1 y. Fourteen term infants with neonatal encephalopathy of gestational age (mean +/- SD) 39.6 +/- 1.6 wk, birth weight 3270 +/- 490 g, underwent MRI and magnetic resonance spectroscopy at 3.5 +/- 2.1 d. Five infants were entered in a pilot study of treatment with moderate whole-body hypothermia for neonatal encephalopathy; two were being cooled at the time of the scan. T(1)- and T(2)-weighted transverse magnetic resonance images were graded as normal or abnormal according to the presence or absence of the normal signal intensity of the posterior limb of the internal capsule and signal intensity changes in the basal ganglia. Localized proton magnetic resonance spectroscopy data were obtained from an 8-cm(3) voxel in the basal ganglia using echo times of 40 and 270 ms, and the peak area ratios of myo-inositol/Cr and lactate/Cr were measured. Outcome was scored using Griffith's development scales and neurodevelopmental examination at 1 y. MRI and outcome were normal in six infants and abnormal in eight. myo-Inositol/Cr and lactate/Cr were higher in infants with abnormal MRI and outcome (p < 0.01, p < 0.01, respectively). myo-Inositol/Cr and lactate/Cr were correlated (p < 0.01) and were both correlated to the Griffith's developmental scales (p < 0.01, p < 0.01, respectively). In conclusion, these preliminary data suggest that early increases in brain basal ganglia myo-inositol/Cr in infants with neonatal encephalopathy are associated with increased lactate/Cr, MRI changes of severe injury, and a poor neurodevelopmental outcome at 1 y.     

Long-term adaptive functioning outcomes of children with inherited metabolic and genetic diseases treated with hematopoietic stem cell transplantation in a single large pediatric center: parents' perspective

Over the past 2 decades, hematopoietic stem cell transplantation (HSCT) has been used as therapy for selected inherited metabolic and genetic diseases (IMGDs). The primary objective of HSCT for these disorders has been to promote long-term survival, optimize quality of life, and improve neurocognitive performance. We performed 45 HSCTs for 44 children with IMGDs (13 related and 32 unrelated); 24 HSCTs for 23 children with Hurler syndrome, 8 for malignant infantile osteopetrosis, 6 for X-linked adrenoleukodystrophy, 2 for metachromatic leukodystrophy, 2 for Gaucher disease, 1 for Ganglioside Monosialic Acid (GM) gangliosidosis, 1 for sialiosis (type 2), and 1 HSCT for Niemann-Pick type A. At a median follow-up of 7.2 years (range: 2.2 to 17.6 y) 18 of 23 patients with Hurler syndrome are alive, 15 attended regular school. Thirteen of 18 were ambulatory, 2 had mobility difficulties, and 1 uses wheelchair. For non-Hurler patients, 5 children suffered secondary graft failure and 4 of them died from progressive disease. The remaining children with osteopetrosis are alive and most children attended regular school. One out of the 4 survivors with adrenoleukodystrophy has been transferred to the adult follow-up clinic and he is in full-time employment. Parents' perspectives and expectations of HSCT in these IMGDs were positive and supportive to continue to offer HSCT for these disorders.     

Proton magnetic resonance spectroscopy reveals medial temporal metabolic abnormalities in adolescents with history of preterm birth

Prematurity is associated with volumetric reductions in specific brain areas such as the hippocampus and with metabolic changes that can be detected by spectroscopy. Short echo time (35 ms) Proton magnetic resonance spectroscopy (1H MRS) was performed to assess possible medial temporal lobe metabolic abnormalities in 21 adolescents with preterm birth (mean age: 14.8, SD: 1.3) compared with an age-matched control sample (mean age: 14.8, SD: 1.6). 1H MRS spectra were analyzed with linear combination model fitting, obtaining the absolute metabolite concentrations for Creatine (Cr), and myo-inositol (Ins). In addition, the following metabolite sums were measured: total Cho (glycerophospho-choline + phosphocholine), total N-acetyl-aspartate + N-acetyl-aspartylglutamate (NA), and total Glx (glutamate + glutamine). A stereological analysis was performed to calculate hippocampal volume. Absolute Cr, and total NA values were decreased in the preterm group (p = 0.016; p = 0.002, respectively). The preterm also showed a hippocampal reduction (p < 0.0001). Significant relationships were found between gestational age and different metabolites and the hippocampal volume. Moreover, hippocampal volume correlated with brain metabolites in the whole sample. Results demonstrate that prematurity affects medial temporal lobe metabolites, and that the alteration is related to structural changes, suggesting that the cerebral changes persist until adolescence.     

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.