Summary: Over the last 15 years, we have performed a total of 30 haematopoietic stem cell transplants on 27 children suffering from Hurler's syndrome. These children were of median age 11 months at the time of diagnosis and 25 months at the time of transplantation. The phenotype was severe in 21 cases (78%). The donor was familial in 13 cases: nine genotypically identical, one phenotypically identical father and three HLA-mismatched donors. Unrelated donors were selected in 17 cases: four phenotypically identical and 13 with 1–4 HLA mismatches. The conditioning regimen generally consisted of busulphan 600 mg/m 2 plus cyclophosphamide (Endoxan ® ) 260 mg/kg and cyclosporin with methotrexate for GvHD prophylaxis. Rabbit anti-thymocyte globulin (Thymoglobuline ® ) was given for all unrelated or familial mismatched transplantations. The median nucleated cell dose infused was 6.00 × 10 8 TNC/kg. No bone marrow (apart from one) was T cell depleted. For first transplants, engraftment was observed in 23/27 patients (pts) (85%). Primary graft failure was observed in 4/27 patients (16%), two were retransplanted from an unrelated donor, one with success. Four patients have died. The primary cause of death was infection in three cases (TRM : 11%) and disease progression in one case, after primary graft failure. Of the 23 living patients, two have disease progression after graft failure and 21 (78%) have functional grafts with a favourable long-term outcome after a median follow-up of 4.7 years, having either full or mixed chimaerism. Among surviving patients with functional grafts, 13 (62%) were transplanted from unrelated donors of whom 10 (77 %) had HLA disparities. There was a remarkably low incidence of GvHD. In our experience, haematopoietic stem cell transplantation using an HLA-matched familial donor or an HLA-matched or -mismatched unrelated donor without T cell depletion or irradiation can achieve a favourable outcome in Hurler's syndrome, with improved cognitive function, but with a limited effect on the corneas and skeleton.

We report our experience in nine patients with Hurler syndrome (six with a severe and three with an intermediate phenotype) who successfully engrafted after bone marrow transplantation. The donor was a human leukocyte antigen-identical sibling in six cases, the human leukocyte antigen-identical father in one case, and an unrelated donor in two cases. One patient with Hurler syndrome and an intermediate phenotype received two successive grafts from the same donor. There was a beneficial effect of bone marrow transplantation on visceral features (hepatosplenomegaly, obstruction of the upper airway, and coarse facies); however, dysostosis multiplex worsened. All patients but one required surgery for carpal tunnel syndrome. Visual acuity was low because of corneal clouding, and two patients had glaucoma several years after the graft. Five patients had normal hearing before graft that remained normal, and four had hearing impairment that improved. All patients had learning difficulties, but none had severe mental retardation (IQ ranging from 75 to 103). The follow-up of patients with severe Hurler syndrome engrafted for more than 10 years emphasizes the limits and benefits of bone marrow transplantation. (J Pediatr 1998;133:119-25)

Four patients with primapterinuria, postulated to be due to pterin-4α-carbinolamine dehydratase (PCD) deficiency, were diagnosed by biochemical and DNA analysis. All four patients presented in the neonatal period with hyperphenylalaninemia, and elevated neopterin and decreased biopterin levels in the urine. These symptoms are common to 6-pyruvoyltetrahydropterin synthase deficiency and thus there is a danger of misdiagnosis. In addition, all four patients had elevated urinary excretion of primapterin (7-biopterin), the only persistent biochemical abnormality. Analysis of fibroblast DNA from the patients identified the following mutations in the PCBD gene: one patient homozygous for the missense mutation E96K and one homozygous for the nonsense mutation Q97X, both in exon 4; one compound heterozygote with the mutations E96K and Q97X; and one patient with two different homozygous mutations: E26X in exon 2 and R87Q in exon 4. In two families, the parents were investigated and found to be obligate heterozygotes for particular mutations. One sibling was found to be unaffected. These results further substantiate the idea that primapterinuria is associated with mutations in the PCBD gene.

Transporteur des acides gras à chaîne longue à l'intérieur de la mitochondrie, la L-carnitine a aussi un rôle très important d'élimination sous forme d'acylearnitines des acyl-CoA accumulés dans la mitochondrie. Tout déficit enzymatique responsable de l'accumulation mitochondriale d'acyl-CoA aboutit à la formation des acylcarnitines correspondantes. La séparation et l'identification des acylcamitines par spectrométrie de masse en tandem dans les milieux biologiques permettent done le diagnostic d'anomalies du métabolisme mitochondrial, et notamment des déficits de l'oxydation des acides gras.

BACKGROUND:L-carnitine is known to transport long chain fatty acids through the mitochondrial membrane but also to export accumulated acyl-CoA's as acylcarnitine esters. Acylcarnitine identification in body fluids allows the diagnosis of mitochondrial inborn errors especially fatty oxidation defects. Tandem mass spectrometry represents a new method for isolation and identification of acylcarnitines in plasma or in blood spotted onto filter paper (Guthrie cards).MATERIAL AND METHODS:In order to validate our method, we studied 30 plasmas from children affected with 15 different inborn errors of metabolism and five amniotic fluids from fetuses affected with several organic acidurias. Fourty-six samples from children at risk for mitochondrial fatty oxidation disorders have been analyzed. We developed a method of tandem mass spectrometry with liquid secondary ion mass spectrometry using deuterated acylcarnitines as internal standards.RESULTS:This method is very sensitive (detection limit = 2 microM). In all affected patients specific acylcarnitine signals corresponding to the metabolic block were constantly found. This confirms the diagnosis and validates the method. Among the 46 at risk children, four defects of long chain fatty acid oxidation were identified.CONCLUSION:This new method is of great interest especially for the long chain fatty acid oxidation defects. These defects are very difficult to diagnose with classical methods as urinary organic acid profiling. A small amount of plasma (100 microL) or blood spotted onto paper is required. The acylcarnitine profile allows a rapid diagnosis if a dedicated apparatus is available.

Background. -L-carnitine is known to transport long chain fatty acids through the mitochondrial membrane bur also to export accumulated acyl-CoA's as acylcarnitine esters. Acylcarnitine identification in body fluids allows the diagnosis of mitochondrial inborn errors especially fatty oxidation defects. Tandem mass spectrometry represents a new method for isolation and identification of acylcarnitines in plasma or in blood spotted onto filter paper (Guthrie cards).Material and methods. - In order to validate our method, we studied 30 plasmas from children affected with 15 different inborn errors of metabolism and five amniotic fluids from fetuses affected with several organic acidurias. Fourty-six samples from children at risk for mitochondrial fatty oxidation disorders have been analyzed. We developed method of tandem mass spectrometry with liquid secondary ion mass spectrometry using deuterated acylcarnitines as internal standards.Results. - This method is very sensitive (detection limit = 2 mu M). In all affected patients specific acylcarnitine signals corresponding to the metabolic block were constantly found. This confirms the diagnosis and validates the method. Among the 46 at risk children, four defects of long chain fatty acid oxidation were identified.Conclusion. - This new method is of great interest especially for the long chain fatty acid oxidation defects. These defects are very difficult to diagnose with classical methods as urinary organic acid profiling. A small amount of plasma (100 mu L) or blood spotted onto paper is required. The acylcarnitine profile allows a rapid diagnosis if a dedicated apparatus is available.

Conclusion Our patient was not an ideal candidate since she was not clinically completely asymptomatic and presented with abnormal MRI and decreased nerve conduction when the metachromatic leukodystrophy was diagnosed in her older sibling. Nevertheless, 2 years after graft the deterioration did not progress and the MRI improved, while her brother became bed‐ridden within few months after the same initial symptoms. These favourable results need further confirmation after several years since significant differences in course have been observed in siblings (Clarke et al 1989).

N-Acetylglutamate synthase (NAGS) deficiency is a rare, autosomal recessive urea-cycle disease. Its clinical presentation is not different from the other hereditary hyperammonaemias. We report a new neonatal case with hyperammonaemic coma. A test by carbamylglutamate was performed at 25 days of life. Since then, the child was treated by carbamylglutamate three or four times a day with a total dose of 80-100 mg/kg per day. Today, the boy is 1 year old. He receives carbamylglutamate 200 mg four times a day. He has normal somatic and neurological development and good metabolic balance.

We report a multiple congenital anomalies (MCA) syndrome in three unrelated fetuses consisting of extremely thin, dense, fishbone-like diaphyses, flared metaphyses, mild micromelic dwarfism, brachydactyly, facial dysmorphism, ocular malformations (microphthalmia, aniridia), cloverleaf skull deformity, and splenic hypoplasia. Histopathological investigations showed abnormalities of the metaphyseal cartilage and adjacent diaphyseal ossification, excessive modelling of the metaphyses, and, in one case, dysplasia of the epiphyseal cartilage. We review three previously reported cases. We suggest the name osteocraniostenosis to describe this radiological and clinical disorder, pinpointing its major clinical and radiological features.

La tyrosinemie hepatorenale ou tyrosinemie de type I est une affection autosomique recessive secondaire a un deficit hepatique et renal en fumarylacetoacetase, indispensable a la derniere etape de degradation de la tyrosine, a l'origine d'une accumulation de maleylacetoacetate, de fumarylacetoacetate et de succinylacetone [1]. Ces produits alterent les fonctions tubulaires renales et inhibent la porphobilinogene-synthetase [2]. L'expression clinique peut etre aigue et souvent mortelle durant les premieres semaines de vie, ou chronique et se revelant par un retard statural, un rachitisme vitaminoresistant et une cirrhose nodulaire

Les auteurs rapportent deux observations familiales de deficit multiple en acyl-CoA deshydrogenases. Chez l'aine, l'affection a debute a l'âge de 9 mois par un syndrome de Reye mortel. Chez son frere, elle a ete reconnue par un diagnostic neonatal, qui a permis la mise en œuvre precoce de mesures preventives

Two new familial cases of 2-ketoglutarate dehydrogenase (2-KGD) deficiency are reported: a girl who died at 10 years and a boy, still alive at 4 years, born to consanguineous parents. The cases developed progressively severe encephalopathy with axial hypotonia, psychotic behaviour, pyramidal symptoms and failure to thrive. Both children exhibited permanent lactic acidosis with acute episodes during emotional stress and various infections, associated with elevated lactate/pyruvate (L/P) ratio and slightly decreased ketone body ratio in plasma. In fibroblasts, the L/P ratio was greatly increased in the boy. No respiratory chain complex deficiency could be demonstrated in cultured fibroblasts or in mitochondria isolated from a muscle biopsy performed on the boy. In muscle isolated mitochondria, a progressive decrease of the rate of glutamate oxidation was observed after ADP addition; the rate of 2-ketoglutarate oxidation was low in the absence of ADP and did not increase after ADP addition. 2-KGD deficiency was demonstrated in fibroblasts from both children and in the boy's muscle and myoblasts. The 2-KGD complex is composed of three separate enzymes: E1, E2 and E3. We could demonstrate in our patient that the E1 and E3 subunits were normal, suggesting that the E2 component could be responsible for the defect.

Human MutationVolume 2, Issue 2 p. 138-140 Mutation in Brief Hunter syndrome: Gene deletions and rearrangements Roseline Froissart, Roseline Froissart Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this authorJean-Luc Blond, Jean-Luc Blond Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this authorIrene Maire, Irene Maire Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this authorPierre Guibaud, Pierre Guibaud Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this authorJohn J. Hopwood, John J. Hopwood Lysosomal Diseases Research Unit, Department of Chemical Pathology, Adelaide Children's Hospital, North Adelaide, Australia; Fax: 78-259-744Search for more papers by this authorMonique Mathieu, Monique Mathieu Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this authorDominique Bozon, Corresponding Author Dominique Bozon Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceCentre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this author Roseline Froissart, Roseline Froissart Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this authorJean-Luc Blond, Jean-Luc Blond Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this authorIrene Maire, Irene Maire Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this authorPierre Guibaud, Pierre Guibaud Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this authorJohn J. Hopwood, John J. Hopwood Lysosomal Diseases Research Unit, Department of Chemical Pathology, Adelaide Children's Hospital, North Adelaide, Australia; Fax: 78-259-744Search for more papers by this authorMonique Mathieu, Monique Mathieu Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this authorDominique Bozon, Corresponding Author Dominique Bozon Centre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceCentre d'Etudes des Maladies Métaboliques, Hǒpital Debrousse, Bǎt. D, 69322 Lyon Cedex 05, FranceSearch for more papers by this author First published: 1993 https://doi.org/10.1002/humu.1380020214Citations: 14AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume2, Issue21993Pages 138-140 RelatedInformation

Principles of dietary management and needs in maple syrup urine disease are well defined. However, long-term results show that there is a need for an improvement of the maintenance of a low plasma leucine level and in monitoring episodes of metabolic decompensation in order to ameliorate the survival and psycho-intellectual outcome.