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Lysosomes are membrane-bound cellular organelles that contain multiple hydrolases needed for the digestion of various macromolecules, including mucopolysaccharides, glycosphingolipids, and oligosaccharides [1]. The lysosomal storage diseases are a group of more than 40 diseases that are characterized by defective lysosomal function leading to an accumulation of specific substrates within the lysosomes and eventual impairment of cellular function. A schematic of the lysosomal system, enzyme trafficking, and substrate accumulation is shown in Figure 30.1. These diseases are classified by the nature of the stored material that results from defects in selected lysosomal enzymes, their cofactors, and/or enzyme or substrate transport (Table 30.1). The lysosomal storage diseases are heterogeneous, progressive, multisystemic diseases that have a spectrum of ages of onset, severity, rates of progression, and organ involvement. Lysosomal storage diseases have significant morbidity and mortality in the absence of effective treatment. The majority of these diseases are autosomal recessive, and although individually each is rare, the combined birth prevalence is approximately 1 in 7000 live births [2]. The diseases are traditionally diagnosed biochemically but in many cases, may also be diagnosed molecularly by the discovery of pathogenic mutations in both copies of the particular gene. The liver is nearly always involved in lysosomal storage diseases; this can be seen at the light or electron microscopic level. The degree of clinical involvement depends on the disorder. In many cases, mild elevations in liver studies and hepatomegaly are the only manifestations. However, significant hepatic injury may be present, resulting in considerable morbidity.

We report a false negative histochemical reaction for myophosphorylase in the case of an 11 year old with fulminant Staphylococcus aureus. Due to increased creatine kinase levels and marked myoglobinuria a muscle biopsy was performed prior to death. The biopsy revealed rhabdomyolysis, glycogen depletion and absent myophosphorylase reactivity. Subsequent myophosphorylase quantification was normal. This unique case of a false negative myophosphorylase histochemical reaction is apparently related to sepsis.

A toddler with a persistent congenital umbilical papule is described. The papule was found to contain both omphalomesenteric and urachal remnants. This patient's findings illustrate the importance of further evaluation of umbilical lesions when conventional therapy with silver nitrate fails.

Objective To devise and test a system with which to evaluate abnormalities on muscle biopsy samples obtained from children diagnosed with juvenile dermatomyositis (DM). Methods We established an International Consensus Group on Juvenile DM Biopsy and carried out 2 phases of consensus process and scoring workshops. Biopsy sections (n = 33) were stained by standard methods. The scoring tool was based on 4 domains of change: inflammatory, vascular, muscle fiber, and connective tissue. Using a Latin square design, biopsy samples were scored by 11 experts for items in each domain, and for a global abnormality measure using a 10-cm visual analog score (VAS 0–10). The tool's reliability was assessed using an intraclass correlation coefficient (ICC) and scorer agreement (α) by determining variation in scorers' ratings. Results There was good agreement in many items of the tool, and several items refined between the meetings improved in reliability and/or agreement. The inflammatory and muscle fiber domains had the highest reliability and agreement. The overall VAS score for abnormality had high agreement and reliability, reaching an ICC of 0.863 at the second consensus meeting. Conclusion We propose a provisional scoring system to measure abnormalities on muscle biopsy samples obtained from children with juvenile DM. This system needs to be validated, and then could be used in prospective studies to test which features of muscle pathology are prognostic of disease course or outcome. We suggest that the process we used could be a template for developing similar systems in other forms of myositis.

Glycogen storage disease type IV (GSD-IV) is an autosomal recessive genetic disorder due to a deficiency in the activity of the glycogen branching enzyme (GBE). A deficiency in GBE activity results in the accumulation of glycogen with fewer branching points and long, unbranched outer chains. The disorder results in a variable phenotype, including musculoskeletal, cardiac, neurological, and hepatic involvement, alone or in continuum, which can be identified at any stage of life. The classic form of GSD-IV is a hepatic presentation, which presents in the first 18 months of life with failure to thrive, hepatomegaly, and cirrhosis that progresses to liver failure, resulting in death by age 5 years. A severe congenital musculoskeletal phenotype with death in the neonatal period has also been described. We report an unusual case of congenital musculoskeletal presentation of GSD-IV with stable congenital hypotonia, gross motor delay, and severe fibro-fatty replacement of the musculature, but no hepatic or cardiac involvement. Molecular analysis revealed two novel missense mutations with amino acid changes in the GBE gene (Q236H and R262C), which may account for the mild phenotype.

Familial hemophagocytic lymphohistiocytosis (HLH) is an autosomal recessive disorder of immune regulation characterized by fever, splenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia, and hyperferritinemia. Although presentation usually occurs during the first 2 years of life, congenital presentation is rare. We report siblings with a presumptive diagnosis of familial HLH who presented with hydrops fetalis and severe hepatic involvement ultimately resulting in their deaths. This report emphasizes the difficulty of confirming the diagnosis of HLH. However, establishing the diagnosis has important implications for genetic counseling and family planning. HLH should be considered in the setting of perinatal liver failure. The immunologic basis of the disease is incompletely understood but testing for natural killer cell function, and perforin defects may be helpful in establishing a diagnosis. HLH can be treated with chemotherapy, immunotherapy, and stem cell transplantation.

Mucosa-associated lymphoid tissue (MALT) lymphoma predominantly occurs in adults, and is rare in children. We report a case of MALT lymphoma involving minor salivary gland of the lip in an otherwise healthy 12-year-old boy. This is the second case report of MALT lymphoma of minor salivary gland in an immunocompetent child. Of 24 cases of MALT lymphomas in children reported in the English literature, parotid MALT lymphomas in human immunodeficiency virus (HIV) patients and H. pylori infection-associated gastric MALT lymphomas are the most common. As in adult cases, most MALT lymphomas in the pediatric age group are localized and follow an indolent clinical course, respond well to therapy, and have an excellent outcome.

Hepatic vascular lesions in pediatric patients have overlapping definitions and a plethora of confusing terminology. The so-called hepatic infantile hemangioendothelioma (IHE) frequently coexists and shares some biological features with cutaneous juvenile hemangioma (CJH). To clarify the nature of hepatic vascular lesions in pediatric patients and to investigate the association between IHE and CJH, we reviewed the clinical features, imaging findings and histopathology of 19 cases of hepatic vascular lesions diagnosed at our institution over the last 33 years. Immunohistochemical stains for a battery of endothelial markers, including GLUT1, were performed. Our results indicate that there are two fundamentally different hepatic vascular lesions in infants and young children: GLUT1-positive hepatic infantile hemangioma (HIH) and GLUT1-negative hepatic vascular malformation with capillary proliferation (HVMCP). The finding of consistent GLUT1 immunoreactivity of endothelial cells in HIH not only offers a powerful tool to distinguish HIH from HVMCP, but also provides immunophenotypic evidence of the similar biological origins of CJH and HIH.

Ubiquinone-responsive multiple respiratory chain dysfunction due to coenzyme Q(10) (CoQ(10)) deficiency has been previously identified in muscle biopsies. However, previous methods are unreliable for estimating CoQ(10) redox status in tissue. We developed an accurate method for measuring tissue concentrations of reduced and oxidized coenzyme Q (CoQ).Mouse tissues were weighed in the frozen state and homogenized with cold 1-propanol on ice. After solvent extraction, centrifugation and filtration, the filtrate was subsequently analyzed by reversed-phase HPLC with coulometric detection.Reference calibration curves were used to determine reduced and oxidized coenzyme Q(9) (CoQ(9)) and CoQ(10) concentrations in tissues. The method is sensitive ( approximately 15 microg/l), reproducible (6% CV) for CoQ(9) and CoQ(10), and linear up to 20 mg/l for CoQ(9) and CoQ(10). Analytical recoveries were 90-104%. In mouse tissues the amounts of total CoQ (TQ) ranged from 261 to 1737 nmol/g of protein. Total CoQ(9) levels are comparable with the values of those previously reported. CoQ is found to be mostly in the reduced form in mouse liver ( approximately 87%), heart ( approximately 60%), and muscle tissues ( approximately 58%); in the brain, most of the CoQ is in the oxidized state ( approximately 65%).This procedure provides a precise, sensitive, and direct assay method for the determination of reduced and oxidized CoQ(9) and CoQ(10) in mouse hindleg muscle, heart, brain, and liver tissues.

Background & Aims: Inborn errors of bile acid metabolism may present as neonatal cholestasis and fat-soluble vitamin malabsorption or as late onset chronic liver disease. Our aim was to fully characterize a defect in bile acid synthesis in a 2-week-old African-American girl presenting with coagulopathy, vitamin D and E deficiencies, and mild cholestasis and in her sibling, whose liver had been used for orthotopic liver transplantation (OLT). Methods: Bile acids were measured by mass spectrometry in urine, bile, serum, and feces of the patient and in urine from the unrelated recipient. Results: Liver biopsy specimens showed neonatal hepatitis with giant cell transformation and hepatocyte necrosis; peroxisomes were reduced in number. High concentrations of (25R)3α,7α,12α-trihydroxy-5β-cholestanoic acid in the urine, bile, and serum established a pattern similar to that of Zellweger syndrome and identical to the Alligator mississippiensis. Serum phytanic acid was normal, whereas pristanic acid was markedly elevated. Biochemical, MRI, and neurologic findings were inconsistent with a generalized defect of peroxisomal function and were unique. Analysis of the urine from the recipient of the deceased sibling's liver confirmed the same bile acid synthetic defect. A deficiency in 2-methylacyl-CoA racemase, which is essential for conversion of (25R)THCA to its 25S-isomer, the substrate to initiate peroxisomal β-oxidation to primary bile acids, was confirmed by DNA analysis revealing a missense mutation (S52P) in the gene encoding this enzyme. Long-term treatment with cholic acid normalized liver enzymes and prevented progression of symptoms. Conclusions: This genetic defect further highlights bile acid synthetic defects as a cause of neonatal cholestasis. GASTROENTEROLOGY 2003;124:217-232

Bile acid synthetic defects are uncommon disorders that cause progressive cholestatic liver disease that is often lethal in infancy or early childhood. Five specific primary defects have been described. Diagnosis is based on mass spectrometry of urine and serum. Pathogenesis of liver injury is related to persistent reduction in levels of normal bile acids and accumulation of abnormal, potentially hepatotoxic, intermediaries. Sites of injury are the liver cell, the bile canaliculus, and the smallest bile ductules. The interlobular bile ducts are normal. The liver lesion is progressive chronic hepatitis with an especially high incidence of GCT in patients who present in infancy. Bile acid replacement therapy is usually effective in arresting the liver injury. Regression of liver damage has been documented during treatment of patients who were diagnosed early in life. Because bile acid synthetic disorders are the only cholestatic diseases of infancy in which GCT of hepatocytes is consistently present, the author suggest that the injury responsible for GCT may be specific for toxic bile acids. Accordingly, immaturity of the bile acid synthetic pathway may render many otherwise normal infants vulnerable to transient "neonatal hepatitis" with GCT in a broad range of cholestatic disorders.

In animal cells, duplication of centrosomes and DNA is coordinated. Since CDK2/cyclin E triggers initiation of both events, activation of CDK2/cyclin E is thought to link these two events. We identified nucleophosmin (NPM/B23) as a substrate of CDK2/cyclin E in centrosome duplication. NPM/B23 associates specifically with unduplicated centrosomes, and NPM/B23 dissociates from centrosomes by CDK2/cyclin E–mediated phosphorylation. An anti-NPM/B23 antibody, which blocks this phosphorylation, suppresses the initiation of centrosome duplication in vivo. Moreover, expression of a nonphosphorylatable mutant NPM/B23 in cells effectively blocks centrosome duplication. Thus, NPM/B23 is a target of CDK2/cyclin E in the initiation of centrosome duplication.

Premature closure of the foramen ovale, 4-chamber cardiac hypertrophy, and renal vein/vena cava thrombosis were found at autopsy of a stillborn dizygotic twin at 36 weeks gestational age. Review of the original prenatal sonograms showed features suggestive of early closure of the foramen ovale. Homozygosity for the 5, 10 methylene tetrahydrofolate reductase mutation was shown only in the affected twin after the parents were found to be heterozygous for the mutation. The difference in outcome of the twins following prenatal treatment with beta mimetics and corticosteroids for preterm labor may be related to the added susceptibility factor for thromboembolism associated with presumed hyperhomocysteinemia in the proband which was not shared by the surviving healthy twin. The role of premature closure of the foramen ovale and prenatal treatment are discussed but remain uncertain.

A case is presented in which autopsy findings (deep groove around the fetal waist and buttock), and gross and microscopic umbilical cord and placental examination (linear ulcer of umbilical cord histologically rimmed by fetal epidermal implants with evidence of remote bleeding) established the diagnosis of umbilical cord encirclement as a cause of intrauterine fetal death despite the lack of prenatal or postnatal obstetrical evidence.

Growth factors are proteins that help regulate the inflammatory response and wound healing in tissues. After laryngotracheal surgery, proper wound healing is important in maintaining the reconstructed airway. The application of growth factor to the respiratory mucosa of the larynx and its effect on wound healing within the airway have not been studied. This study was designed to establish a model for the evaluation of wound healing after the application of growth factor to composite respiratory mucosa and cartilage surfaces at the time of laryngotracheoplasty. Forty rabbits underwent anterior cricoid cartilage split with or without the use of a cartilage graft. Platelet-derived growth factor or a placebo substance was applied to the wound at the time of surgery. This study offers a model for studying wound healing in the airway that is reproducible with limited morbidity. (Otolaryngol Head Neck Surg 1999;120:78-83.)

To examine the relationship between hepatotoxic risk factors and liver histopathology in patients with juvenile rheumatoid arthritis (JRA) treated with methotrexate (MTX).We graded the histology of 33 percutaneous liver biopsy specimens from 25 patients with JRA treated at Children's Hospital Medical Center, Cincinnati, Ohio, using the Roenigk Classification Scale. Stepwise linear and logistic regression analyses were performed to examine the relationship of the Roenigk grade and presence of liver fibrosis of biopsy specimens with potential risk factors.Twenty-seven biopsy specimens (82%) were classified as grade I, 4 (12%) as grade II, and 2 (6%) as grade IIIA; none demonstrated significant fibrosis. The frequency of biochemical abnormalities (P.001) and body mass index (P =.05) were the only risk factors found to significantly relate to the Roenigk grade. The following factors were not significantly associated with the Roenigk grade: age, gender, disease duration, JRA subtype and course, duration of MTX administration, weekly MTX dose, cumulative dose of MTX, route of MTX administration, use of folic acid supplementation, concurrent use of other medications, and potential hepatotoxic comorbidities.Serial biochemical abnormalities are significantly associated with Roenigk grade and the presence of liver fibrosis. These findings concur with studies of patients with rheumatoid arthritis, suggesting that guidelines for monitoring MTX hepatotoxicity in rheumatoid arthritis may be applicable to patients with JRA.

Objective. To determine if the long-term use of methotrexate (MTX) in juvenile rheumatoid arthritis (JRA) is associated with the development of significant liver fibrosis, and to describe the presence of risk factors for liver fibrosis in patients with JRA. Methods. Needle biopsies of the liver were performed on a cross-section cohort of 14 patients with JRA who had received a total cumulative dose of MTX that was either >3,000 mg or >4,000 mg/1.73 m2 of body surface area. Biopsy samples were independently graded according to the Roenigk Classification Scale by 2 pathologists. The presence of risk factors for MTX hepatotoxicity, especially biochemical abnormalities reflective of liver injury and alcohol consumption, were assessed. Results. Thirteen biopsy samples (93%) were classified as grade I, and 1 (7%) as grade II; none demonstrated significant fibrosis. However, histologic abnormalities were found in 13 biopsy samples (93%). Only 2 patients (14%) consumed more than 1 alcoholic drink per month. Thirteen patients (93%) had biochemical abnormalities while being treated with MTX, but only 5 patients (36%) had at least 1 determination in which the aspartate or alanine aminotransferase elevation was >3 times the upper limit of normal. Conclusion. Long-term use of MTX for JRA does not appear to be associated with the development of significant liver fibrosis. Although nearly all patients had minor histologic changes, no significant clinical consequences were apparent. A prospective study of a larger population will more accurately define the incidence of MTX-related liver fibrosis and appropriate monitoring guidelines in JRA.

Background & Aims The final step in bile acid synthesis involves conjugation with glycine and taurine, which promotes a high intraluminal micellar concentration to facilitate lipid absorption. We investigated the clinical, biochemical, molecular, and morphologic features of a genetic defect in bile acid conjugation in 10 pediatric patients with fat-soluble vitamin deficiency, some with growth failure or transient neonatal cholestatic hepatitis. Methods We identified the genetic defect that causes this disorder using mass spectrometry analysis of urine, bile, and serum samples and sequence analysis of the genes encoding bile acid-CoA:amino acid N -acyltransferase (BAAT) and bile acid-CoA ligase (SLC27A5). Results Levels of urinary bile acids were increased (432 ± 248 μmol/L) and predominantly excreted in unconjugated forms (79.4% ± 3.9%) and as sulfates and glucuronides. Glycine or taurine conjugates were absent in the urine, bile, and serum. Unconjugated bile acids accounted for 95.7% ± 5.8% of the bile acids in duodenal bile, with cholic acid accounting for 82.4% ± 5.5% of the total. Duodenal bile acid concentrations were 12.1 ± 5.9 mmol/L, which is too low for efficient lipid absorption. The biochemical profile was consistent with defective bile acid amidation. Molecular analysis of BAAT confirmed 4 different homozygous mutations in 8 patients tested. Conclusions Based on a study of 10 pediatric patients, genetic defects that disrupt bile acid amidation cause fat-soluble vitamin deficiency and growth failure, indicating the importance of bile acid conjugation in lipid absorption. Some patients developed liver disease with features of a cholangiopathy. These findings indicate that patients with idiopathic neonatal cholestasis or later onset of unexplained fat-soluble vitamin deficiency should be screened for defects in bile acid conjugation.

Independent nephrogenic rests (NRs) accompany many Wilms tumors (WTs), exhibit a range of qualities suggesting dormancy, maturation, regression, and hyperplasia, and may carry the WT-1 mutation. We assessed nucleolar organizer regions, proliferating cell nuclear antigen (PCNA) activity, cytoplasmic filament expression, and nuclear morphology in 79 nephrogenic rests accompanying 20 WTs. We found a direct relationship between the size of a blastematous NR and the AgNOR number per nucleus and a close correlation with PCNA activity. The blastema of most NRs1 cm in diameter was indistinguishable from blastema of most WTs. The smallest NR usually had a low number of silver-reactive nucleolar organizing regions (AgNORs), low PCNA activity, and absent cytoplasmic filaments, all characteristics of a nascent dormant state in which both proliferation rate and protein synthetic activity are low. Intermediate filament expression was variable in blastema of larger NRs; cytoplasmic filaments correlated with emergence of epithelial maturation and absence of filaments with accumulation of immature cells; mature epithelial structures in NRs had low AgNOR number and PCNA activity representing a terminal dormant state. The majority of blastemal cells in most WTs and in one-third of large hyperplastic NRs lack cytoplasmic filaments. This, plus the occasional finding in large NRs of features more typical of WTs such as prevalence of apoptosis, patches of frank necrosis, multinodular architecture, and expanses of monomorphic, poorly vascularized blastema with low PCNA activity, suggest that it may be possible to distinguish NRs that are progressing toward WT from those that are merely hyperplastic. This study refines the concepts of dormancy and hyperplasia as expressed in NRs and provides a general framework for probing the relationship of molecular events to progression of a small proportion of NRs to WT. Criteria used herein to define dormancy and hyperplasia may be useful in assessing lesions other than typical WT, such as unusually large or extensive NRs or uncommon differentiated WTs where the potential for aggressive behavior may be lower than in usual WTs.

Background & Aims Pathologists participating in the National Institutes of Health–sponsored Biliary Atresia Research Consortium (BARC) developed and then evaluated a standardized system for histologic reporting of liver biopsies from infants with cholestasis. Methods A set of 97 anonymous liver biopsy samples was sent to 10 pathologists at BARC centers. A semiquantitative scoring system that had 16 histologic features was developed and then used by the pathologists, who had no knowledge of clinical history, imaging results, or laboratory data. Interobserver agreement was evaluated statistically. Agreement on scoring of each feature and on the pathologists' diagnosis, compared with the final clinical diagnosis, was evaluated by using weighted kappa statistics. Results There was moderate to substantial interobserver agreement in identification of bile plugs in ducts, giant-cell transformation, extramedullary hematopoiesis, and bile duct proliferation. The pathologists' diagnosis of obstruction in clinically proven cases of biliary atresia (BA) ranged from 79%–98%, with a positive predictive value of 90.7%. Histologic features that best predicted BA, on the basis of logistic regression, included bile duct proliferation, portal fibrosis, and absence of sinusoidal fibrosis (each P Conclusions The BARC histologic assessment system identified features of liver biopsies from cholestatic infants, with good interobserver agreement, that might be used in diagnosis and determination of prognosis. The system diagnosed BA with a high level of sensitivity and identified infants with biliary obstruction with reasonable interobserver agreement. However, distinguishing between BA and disorders such as total parenteral nutrition–associated liver disease and alpha 1 -antitrypsin deficiency is not possible without adequate clinical information.

Background Young age at portoenterostomy has been linked to improved outcome in biliary atresia, but pre-existing biological factors may influence the rate of disease progression. In this study, we aimed to determine whether molecular profiling of the liver identifies stages of disease at diagnosis. Methods We examined liver biopsies from 47 infants with biliary atresia enrolled in a prospective observational study. Biopsies were scored for inflammation and fibrosis, used for gene expression profiles, and tested for association with indicators of disease severity, response to surgery, and survival at 2 years. Results Fourteen of 47 livers displayed predominant histological features of inflammation (N = 9) or fibrosis (N = 5), with the remainder showing similar levels of both simultaneously. By differential profiling of gene expression, the 14 livers had a unique molecular signature containing 150 gene probes. Applying prediction analysis models, the probes classified 29 of the remaining 33 livers into inflammation or fibrosis. Molecular classification into the two groups was validated by the findings of increased hepatic population of lymphocyte subsets or tissue accumulation of matrix substrates. The groups had no association with traditional markers of liver injury or function, response to surgery, or complications of cirrhosis. However, infants with an inflammation signature were younger, while those with a fibrosis signature had decreased transplant-free survival. Conclusions Molecular profiling at diagnosis of biliary atresia uncovers a signature of inflammation or fibrosis in most livers. This signature may relate to staging of disease at diagnosis and has implications to clinical outcomes.

To study the biology of bladder mucosal grafts we developed an animal model using New Zealand white male rabbits. A 25 x 9 mm. segment of bladder mucosa was harvested and tubularized over an 8F catheter using 7-zero polyglactin sutures. An equivalent portion of rabbit urethra was then excised and the graft was anastomosed to this defect in an end-to-end fashion. A urethral catheter was left in place to provide bladder drainage and to stent the anastomosis. Animals were sacrificed on postoperative days 1 to 90. India ink was injected into the aorta at sacrifice to visualize the microvasculature. All 59 specimens were stained with hematoxylin and eosin, and studied using light microscopy. Our results demonstrated vascular ingrowth at 72 hours. Between postoperative days 8 and 10 healthy viable epithelium first bridged the entire urethral defect. By postoperative day 12 the epithelial lining was complete. A poor outcome was observed in all animals whose stents were removed early. We conclude that the biology of bladder mucosal grafts is unique in that the graft initially undergoes partial degeneration followed by regeneration. Of concern are the results of those animals whose stents were removed early. In all such cases a poor outcome was observed.

Tracheal cartilaginous sleeve (TCS) is a rare congenital malformation in which discrete cartilaginous rings are replaced by a grossly uninterrupted cartilaginous sleeve. Seven previous patients with TCS have been reported in the world literature; in each instance, TCS was associated with craniosynostosis (CS). We report details of five additional patients with TCS, of whom four had a dominantly inherited CS. Gross examination of the available tracheas and bronchi demonstrates a cartilaginous sleeve with posterior interruption but lacking a normal pars membranacea. The stained and cleared tracheas all demonstrate variable ring formation, usually limited to the posterolateral aspect. The functional significance of TCS, if any, is unknown. No data are available on the prevalence of TCS in CS syndromes. The formation of TCS implies a common mesenchymal defect in which normally discrete structures fuse and is probably analogous to other mesenchymal abnormalities seen in these patients.

IN adults, deficiency of carnitine palmitoyltransferase (CPT) II is a genetic disorder characterized by exercise intolerance and myoglobinuria.1 , 2 In newborns, it is a generalized, lethal disease with reduced CPT II activity in multiple organs, reduced concentrations of total and free carnitine, and increased concentrations of lipids and long-chain acylcarnitines.3 The clinical severity of CPT II deficiency is not determined by the degree of the reduction in CPT II activity, since this reduction is of similar magnitude in adults, young children, and newborns.1 2 3 4 5 However, lethal CPT II deficiency is associated with an accumulation of arrhythmogenic long-chain acylcarnitines,6 , 7 as in the patient . . .

Down syndrome (DS) is not usually thought of in association with significant infantile liver disease. We present clinical and histopathologic data from 10 patients with DS who presented with severe liver disease at birth or within the first few weeks of life, and summarize the findings of eight previously reported cases. The liver disease was fatal in all but one case. Diffuse lobular fibrosis surrounding proliferating ductular elements and residual hepatocytes characterized the pathologic findings in the liver in all patients. A large number of megakaryocytes were present in the liver in nine of 12 patients. The phenotype of "perinatal hemochromatosis" was documented in eight of nine cases in which the presence of iron was investigated. Since only a fraction of the patients with this phenotype have DS, the patients we describe seem to represent a relatively well-defined subset of the perinatal hemochromatosis phenotype. The existence of such a subset suggests that the perinatal hemochromatosis phenotype does not represent a single etiopathogenetic disorder. The association between DS, megakaryocytic infiltrates in the liver, and fatal subacute/chronic liver disease gives rise to the speculation that fibrosis-promoting factors and/or metabolic abnormalities, such as those resulting from a gene dosage effect, may play a role in the genesis of the liver disease, perhaps due to a particular susceptibility of fetal liver.

A rare window type of patent ductus arteriosus is reported that was large (15 mm in maximal transverse dimension) but had virtually no length and hence was externally invisible. The smaller aortic isthmus (4 mm in diameter), which was intrapericardial, was mistaken for the ductus and was inadvertently clip-occluded, leading to death. After a specific diagnosis is made, the large window ductus should be patched on cardiopulmonary bypass with a transpulmonary approach.

Three unrelated patients had Vmax normal for CPT I but reduced for CPT II, and normal Km for both. Palmitoyl CoA synthase, carnitine acetyl transferase, 4 acyl CoA dehydrogenases were normal. The patients: (1) A girl died at 5 days of encephalo-cardiomyopathy. Lipid was high in heart, liver, muscle; in these and in fibroblasts. CPT II was < 6% or not detectable. Total Carnitine was low, acyl carnitine high (Hug el al.Pediatr Res 25:115A;1989). (2) A male without muscle symptoms died at 20 years of dilated cardiomyopathy, as did his half-brother (of a different father). In heart, lipid was not excessive, carnitine was 50% and CPT II was 19%. (3) A male at 20 years had symptoms as in muscle CPT deficiency (DiMauro et al.Science 182:929;1973). Liver and heart were normal clinically. CPT II was 6% in muscle and fibroblasts. - Deficient CPT II and normal CPT I in the same patient indicate thai the 2 enzymes differ. Whether different phenotypes in CPT deficiency reflect differences in tissue distribution and in extent of the defect must be studied in multiple tissues obtained at biopsy or autopsy.

SODIUM valproate, a recently introduced anticonvulsant, is particularly useful in the management of absence seizures and has gained widespread popularity.1 Initial European studies reported infrequ...