Unusual gallbladder findings in two brothers with metachromatic leukodystrophy

Characteristic biliary tree abnormalities in metachromatic leukodystrophy (MLD) include gallbladder polyposis and haemobilia. We report two brothers with MLD, who presented with uncommon biliary complications. One presented with gastric outlet obstruction secondary to gallbladder enlargement, which was treated by percutaneous aspiration. He later developed gallbladder carcinoma with liver metastases. His brother demonstrated US findings consistent with gallstones. Received: 20 August 1997 Accepted: 23 February 1998     

THE INCIDENCE AND GENETICS OF METACHROMATIC LEUCODYSTROPHY IN NORTHERN SWEDEN

The purpose of this study was to investigate the incidence and genetics of metachromatic leuco-dystrophy (MLD). A series of 13 cases of late infantile MLD and 2 cases of juvenile MLD was collected from the northern part of Sweden and studied together with their relatives. The series was considered to be adequately representative of the true occurrence of MLD during the period 1955–1965. The incidence rate for late infantile MLD was estimated to be about 1 per 40 000. The MLD patients were highly concentrated to the south-west part of Norrland. From the family analysis it was concluded that late infantile MLD is most probably transmitted by an autosomal recessive gene.     

Peripheral neuropathy as the sole initial finding in three children with infantile metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is a progressive white matter disease caused by arylsulfatase A deficiency. Demyelination in the nervous system is detected by cerebral magnetic resonance imaging (MRI) and neurophysiological studies.We present three children with infantile MLD, who had difficulties in standing and walking with absent reflexes. Protein levels in cerebral spinal fluid (CSF) were elevated and nerve conduction studies revealed slowing down of motor nerve conduction velocity. Initial cerebral MRIs showed no white matter changes. Consecutively, all three children developed clinical symptoms of neurodegenerative disease. Follow-up MRI and arylsulfatase A testing led to diagnosis of MLD.We conclude, that in young children who present with an acute/subacute demyelinating polyneuropathy, MLD is a differential diagnosis.     

THE RELIABILITY OF THE DIAGNOSIS OF METACHROMATIC LEUCODYSTROPHY BY PERIPHERAL NERVE BIOPSY

In order to increase the certainty of the diagnosis from peripheral nerve biopsy in cases of suspected metachromatic leucodystrophy, peripheral nerves were examined from individuals belonging to three different categories, viz. cases of metachromatic leucodystrophy (MLD) verified chemically and post-mortem, cases of other diseases afflicting the peripheral nerves, and cases with no clinical or morphological evidence of neurological disease. The method recommended for the diagnostic establishment of sulphatides is that described by v. Hirsch & Peiffer, with cresyl violet and acetic acid applied to frozen sections. Using this method the sulphatides appear as brown metachromatic granular substances, which are completely dissolved by chloroform and methanol. The most important results of the present investigation can be summarized as follows: 1. In advanced cases of MLD there is a copious accumulation of a yellow-brown metachromatic granular substance localized partly to Schwann cells, partly to perivascular or subperineurial phagocytes. In addition, there are advanced axon and myelin lesions. .2. In peripheral neuropathies due to causes other than MLD and in normal peripheral nerves, there are also varying amounts of brown metachromatic granules localized to nerve fibres. However, no massive accumulation occurs in perivascular or subperineurial phagocytes. For the present, a reliable diagnosis of MLD by peripheral nerve biopsy requires the demonstration of sulphatide accumulation in typical phagocytes. In those cases in which the brown metachromatic substance can only be traced to nerve fibres and Schwann cells, no reliable diagnosis of MLD can be made, but neither can the possibility of an early stage of MLD be excluded.     

Gene therapy for metachromatic leukodystrophy

Metachromatic leukodystrophy (MLD) is an inherited metabolic disease which is characterized by a deficiency of arylsulfatase A (ASA). This deficiency causes progressive accumulation of cerebroside sulfate in oligodendrocytes (OL) in the brain, resulting in dysmyelination. Approaches being developed by the authors to treating MLD are based on direct delivery of ASA genes into the brain. In the present report, it has been shown that the recombinant adenovirus (Adex 1SRLacZ) was able to transduce the OL very efficiently. Moreover, primary fibroblasts from MLD patients were exposed to recombinant adenovirus expressing the ASA gene (Adex1SRASA) and the cells expressed the transgene. The influence of overexpression of ASA on the activity of other sulfatases was also tested in fibroblasts from patients with MLD using a retrovirus vector (MFG-ASA). It was demonstrated that the overexpression of ASA reduces the activity of various sulfatases by a small amount but does not induce an accumulation of glycosaminoglycan. These results indicate that the influence of ASA overexpression on other sulfatases is different from that of the N-acetygalactosamine-4-sulfatase overexpression in a previous report. It was concluded that the correction of ASA deficiency by a recombinant adenovirus that potentially could be used to transfer the gene to the brain, and gene therapy for MLD based on gene transfer of the ASA gene to mutant cells will be feasible because the overexpression of ASA in cells does not lead to profound deficiency of other sulfatases or result in a new phenotype.     

Prenatal diagnosis of metachromatic leukodystrophy in a family with pseudo arylsulfatase A deficiency by the cerebroside sulfate loading test

Prenatal diagnosis was requested by a family at risk for metachromatic leukodystrophy (MLD). An examination of the family leukocyte arylsulfatase A profile revealed that the mother had pseudo arylsulfatase A deficiency. Cultured amniotic fluid cells were deficient in arylsulfatase A, so two possibilities were indicated: the fetus was affected with MLD or had the pseudodeficiency phenotype. The only known biochemical test to differentiate the two enzyme deficient phenotypes is cerebroside sulfate loading of growing fibroblasts. The pseudodeficient cells hydrolyze the incorporated sulfatide as efficiently as control cells, whereas MLD cells show no hydrolysis. Application of this test to the at risk cultured amniotic fluid cells resulted in appreciable uptake of the sulfolipid, but no hydrolysis. Control amniotic fluid cell cultures hydrolyzed 82 to 95% of the incorporated sulfatide. Therefore, an affected fetus was indicated. Fibroblasts derived from the aborted fetus showed a deficiency of arylsulfatase A and a similar inability to hydrolyze cerebroside sulfate in the loading test. The loading technique allowed the prenatal diagnosis of MLD when the arylsulfatase A analysis was equivocal.     

The relationship between vocabulary, grammar, and false belief task performance in children with autistic spectrum disorders and children with moderate learning difficulties

BACKGROUND: The aim of this study was to examine the relationship between language and theory of mind in children with autistic spectrum disorders (ASD) and children with moderate learning difficulties (MLD). Previous studies have found a strong association between language and theory of mind in a range of groups, but mostly have not included measures of both grammar and vocabulary; including these enables us to speculate about the causal direction of the relationship. METHODS: Fifty-eight children with ASD and 118 children with MLD were given standardised assessments of vocabulary and grammar, along with standard theory of mind tasks. RESULTS: The relationship between language and theory of mind was more evident in children with ASD than in those with MLD, and grammar was a particularly strong predictor of theory of mind performance in children with ASD. Children with MLD performed better on false belief (FB) tasks than did children with ASD, and their performance was more predictable across the different theory of mind tasks. CONCLUSIONS: Language, in particular grammar, and theory of mind appear to be more strongly related in children with ASD than in those with MLD. We speculate that this relationship may be causal, with some grammatical understanding being a precursor of theory of mind. The implications of these findings are discussed in relation to possible routes for compensatory strategies for mentalising in children with ASD.     

Studies on Cerebral Lipidosis Enzymatic Diagnosis of Metachromatic Leukodystrophy*

Leucocyte arylsulfatase A activity of four patients with MLD and their families were studied. The patients showed marked decrease of enzyme activity and their parents showed significantly lower activity than normal adults. These findings suggest that leucocyte arylsulfatase A activity is useful not only for the diagnosis of patients with MLD but for the detection of carrier state.     

Diffuse juvenile non-adenomatous polyposis: a rare cause of severe hypoalbuminaemia in childhood

Hypoalbuminaemia is a well-recognized complication of juvenile polyposis, which is often not clinically apparent. We describe a child with diffuse colonic non-adenomatous polyposis who presented with generalized oedema and severe hypoalbuminaemia. The site of the protein loss was the polyps, and the problem resolved after colectomy. This is a case of unusually severe hypoalbuminaemia complicating juvenile polyposis.     

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。     

Metachromatic leucodystrophy: review of 38 cases.

Clinical and laboratory features of 38 children suffering from metachromatic leucodystrophy (MLD) are reported. Twenty-four children with the late infantile form of MLD presented between ages 6 and 25 (mean 17) months with a delay or deterioration in walking, followed by a general loss of abilities. There was severe handicap by age 3 years and death occurred between 5 months and 8 years after presentation. Neurological signs at the time of diagnosis were varied. Motor nerve conduction velocity was slowed in the 18 children tested. The disease became evident at a later age in 14 children. One boy presented at 13 years, while in the remainder there appeared to be two clinical patterns of the disease which could be termed (1) early juvenile or intermediate and (2) juvenile MLD. In 7 children with early juvenile or intermediate MLD a gait disorder developed between ages 4 and 6 (mean 5) years. This was accompanied in 4 children, and followed between 8 and 26 months later in the remaining 3, by loss of other abilities. Neurological signs were varied. Motor nerve conduction velocity was slowed in 2 of the 5 patients tested. Six children with juvenile MLD presented between ages 6 and 10 years with educational or behavioural difficulties. Motor disorders arose from 6 months to 4 years later. Neurological signs at the time of diagnosis, although mixed, were predominantly extrapyramidal and motor nerve conduction velocity was slowed in 2 of the 3 children tested. In the early juvenile form of MLD, progression of the disease was slower than in the late infantile form and death occurred between 31/2 and 18 years after presentation. Only one-third of patients had fits and these tended to be a late feature.     

Giant inflammatory polyposis coli as a manifestation of Crohn's disease in patients with coexistent cystic fibrosis.

Crohn's disease (CD) arising in children with cystic fibrosis (CF) is well recognized. Indeed, reports suggest that CD is significantly more common in patients with CF than in the general population. Giant inflammatory polyposis is a rare manifestation of idiopathic inflammatory bowel disease and may complicate both ulcerative colitis and CD. Giant inflammatory polyposis has not been specifically reported in patients with coexistent CF and CD. Herein, we report the occurrence of giant inflammatory polyposis in 2 boys attending a tertiary care hospital, with an established diagnosis of CF who subsequently developed CD. Both boys required surgical treatment for CD. In addition to classical features of CD, both colonic resection specimens showed giant inflammatory polyposis. The appearances were modified by the presence of a layer of thick mucus. It is suggested that the coexistence of CF in patients with CD may predispose to the development of giant inflammatory polyposis. In addition to contributing to their development, it also appears that there is a propensity for CF to alter the morphological appearance of giant inflammatory polyposis. This may lead to diagnostic confusion when examining endoscopic biopsies.     

Polyposis of the gallbladder associated with metachromatic leukodystrophy

We report on two children with metachromatic leukodystrophy and polyposis of the gallbladder. In both patients ultrasound examination revealed a small gallbladder with a thickened echogenic wall and multiple polypoid masses. In one patient diagnosis of gallbladder polyposis was made 6 months before the first neurological symptoms occurred. As gallbladder polyposis is a rare phenomenon in childhood, metachromatic leukodystrophy should be excluded.     

Consequences, characteristics, and causes of mathematical learning disabilities and persistent low achievement in mathematics

The goals of the review are threefold: (a) to highlight the educational and employment consequences of poorly developed mathematical competencies; (b) overview the characteristics of children with mathematical learning disability (MLD) and with persistently low achievement (LA) in mathematics; and (c) provide a primer on cognitive science research that is aimed at identifying the cognitive mechanisms underlying these learning disabilities and associated cognitive interventions. Literatures on the educational and economic consequences of poor mathematics achievement were reviewed and integrated with reviews of epidemiological, behavioral genetic, and cognitive science studies of poor mathematics achievement. Poor mathematical competencies are common among adults and result in employment difficulties and difficulties in many common day-to-day activities. Among students, ～ 7% of children and adolescents have MLD and another 10% show persistent LA in mathematics, despite average abilities in most other areas. Children with MLD and their LA peers have deficits in understanding and representing numerical magnitude, difficulties retrieving basic arithmetic facts from long-term memory, and delays in learning mathematical procedures. These deficits and delays cannot be attributed to intelligence but are related to working memory deficits for children with MLD, but not LA children. These individuals have identifiable number and memory delays and deficits that seem to be specific to mathematics learning. Interventions that target these cognitive deficits are in development and preliminary results are promising.     

Familial Adenomatous Polyposis Coli and Clear Cell Sarcoma of the Kidney

Familial adenomatous polyposis coli is an inherited multiple neoplasia syndrome that is associated with an increased risk for development of another primary tumor. We report a case of a 14-year-old boy who had a proctocolectomy for familial adenomatous polyposis coli. He had survived radical nephrectomy, chemotherapy, and radiotherapy for a congenital clear cell sarcoma of the right kidney. Perhaps the presence of the familial adenomatous polyposis gene induces chromosomal instability in affected persons.     

Generalized juvenile polyposis in an infant: report of a case and successful management by endoscopy

A case of juvenile gastrointestinal polyposis in an infant is described and the literature is reviewed. Major clinical problems are related to the extent of the juvenile polyposis. The disease has a poor prognosis. The endoscopic techniques used when polyposis is limited allow histologic evaluation of the polyps and conservative treatment.     

Metachromatic leukodystrophy without arylsulfatase A deficiency.

Two siblings of consanguinous parents were noted to have a neurologic syndrome marked by developmental delay, regression of psychomotor performance, marked spasticity and progressive central nervous system degeneration. Markedly delayed nerve conduction times and a sural nerve biopsy which demonstrated changes typical of metachromatic leukodystrophy (MLD) were evident. Impairment of sulfated glycolipid metabolism was documented by analysis of glycospingolipid in urinary sediment. In spite of these findings, activities of arylsulfatase A and cerebroside sulfatidase in white blood cells and cultured skin fibroblasts were near normal. However, when intact growing fibroblasts were loaded with 35SO4-sulfatide a clear defect in sulfatide cleavage, comparable to that seen in MLD patients, was observed. Thus, these patients represent a new form of sulfatide storage disease -- MLD characterized by intact enzyme activity in cell homogenates but defective sulfolipid metabolism in vivo and in intact fibroblasts.     

Does idiopathic naso-sinusal polyposis exist in children?]

Nasal polyposis, a rare disease in childhood, can present itself as an idiopathic disease. The aim of this study was to describe some of the clinical features of idiopathic nasal polyposis in children and to emphasize this condition as a specific clinical entity. POPULATION AND METHODS: The study was based on a retrospective analysis of 26 cases of idiopathic nasal polyposis that were studied to our department between 1979 and 1996. In addition, a questionnaire was sent to parents of which 20 were returned completed. RESULTS: The clinical characteristics of idiopathic nasal polyposis in children (11 males and nine females; median: 12 years; range: 8-15 years) were very similar to those observed in adults (median: 50 years), in particular the relation to asthma (ten of 20 cases) and aspirin intolerance (two Fernand-Widal syndromes of 20 cases). Recurrent ENT infections during the maturing period of the immunological system (0-7 years) did not seem to play a role. There appeared, however, to be a strong genetic component as half of our cases had a family history of nasal polyposis and/or asthma. DISCUSSION: Idiopathic nasal polyposis should be recognized as an entity among nasal polyps in childhood. Management of idiopathic and secondary nasal polyposis is however different. Although the pathogenesis of nasal polyposis is not well understood, the study of this disease in children leads one to suspect a genetic transmission.     

Rhabdomyosarcoma associated with familial adenomatous polyposis

We report a case of a 16 year old girl with orbital rhabdomyosarcoma who during chemotherapy developed bloody diarrhoea. On investigation she was found to have multiple colonic polyps. Cytogenetic analysis has shown a pattern typical of familial adenomatous polyposis. We present a review of the literature concerning the associations of familial adenomatous polyposis. The association of familial adenomatous polyposis with rhabdomyosarcoma has not been previously reported.