A rare malignant hepatic tumor of childhood: transitional liver cell tumor revisited.

Transitional liver cell tumor is an extremely rare entity and has a poor prognosis. It has similar histopathologic findings with hepatoblastoma and hepatocellular carcinoma. Up to now, only 10 cases have been reported in the literature. We report on an 8-year-old boy with histologically proven transitional liver cell tumor and describe the pertinent radiological findings.

Demyelinating disease of central and peripheral nervous systems associated with a A8344G mutation in tRNALys.

We describe a patient with acute combined demyelinating disease of the central and peripheral nervous systems associated with the A8344G mutation in the mitochondrial tRNA lysine gene. A 7-year-old boy presented with acute onset of palpitations, tinnitus, ataxia, bilateral sixth nerve palsy, and flaccid quadriparesis. Serum creatine kinase and lactate were mildly increased. Electromyography showed demyelinating sensory and motor polyneuropathy. Brain magnetic resonance imaging demonstrated demyelination in the left thalamus and magnetic resonance spectroscopy revealed a lactate peak corresponding to this lesion. Histologic analysis of the muscle showed cytochrome c-oxidase-deficient fibers and ragged red fibers. Respiratory chain analyses revealed deficiencies of complexes I and IV. Molecular genetic analyses of the muscle showed an A8344G (MERRF) mutation in mitochondrial tRNA lysine. To the best of our knowledge, this is the first description of this mutation associated with acute combined demyelinating disease of the central and peripheral nervous systems.

Myogenesis within the human gubernaculum: histological and immunohistochemical evaluation.

BACKGROUND: The presence of varying amounts of smooth muscle (SM) in the patent processus vaginalis suggests that SM plays a role in the descent of the testis. Myogenesis within the gubernaculum (representing primitive mesenchymal tissue) has been evaluated. MATERIALS AND METHODS: Bilateral gubernacula of ten male and five female fetuses were obtained. Sections were stained with hematoxylin-eosin, van Gieson and Gomori trichrome. Expressions of human muscle actin, desmin, vimentin, alpha-smooth muscle actin, human myosin, fast myosin, slow myosin, and Myo-D were determined through immunohistochemistry. The structural alterations and expressions according to the fetal ages were determined within the gubernacula of both sexes. RESULTS: Gubernacula revealed striated muscle at twelve weeks of age. Despite expression of actin and desmin, those muscles did not express Myo-D. Actin and desmin expressing striated muscles ceased to exist until 22 weeks of age. Both vascular SM and cremaster muscle (CM) expressed Myo-D during the 22nd and 23rd weeks. CM additionally expressed alpha-smooth muscle actin. Detection of myofibroblasts in the 22nd week was followed by appearance of the SM in the 27th week in the gubernacula of male fetuses. The same alterations were encountered among the female fetuses at later time points. CONCLUSION: Both smooth muscle and CM develop within the gubernaculum. CM may have transdifferentiated from the vascular SM. If the gubernaculum represents primitive mesenchymal tissue, it ceases to exist after the development of muscles.

Two patients with 'Dropped head syndrome' due to mutations in LMNA or SEPN1 genes.

Dropped head syndrome is characterized by severe weakness of neck extensor muscles with sparing of the flexors. It is a prominent sign in several neuromuscular conditions, but it may also be an isolated feature with uncertain aetiology. We report two children in whom prominent weakness of neck extensor muscles is associated with mutations in lamin A/C (LMNA) and selenoprotein N1 (SEPN1) genes, respectively. This report expands the underlying causes of the dropped head syndrome which may be the presenting feature of a congenital muscular dystrophy.

An experimental study of choleretic effect and histopathologic alterations in the gastrointestinal system after whole-bowel irrigation.

BACKGROUND/PURPOSE: Whole-bowel irrigation (WBI) has been used for different purposes. It has been the preferred method of bowel cleansing before large bowel surgery and colonoscopy. There are some studies about histopathologic alterations in the gastrointestinal system caused by WBI. It was reported that large quantities of bile-stained intraluminal fluid were seen after WBI with lactated Ringer's solution. In light of all these studies, the authors have decided to inspect whether WBI is choleretic and whether the histopathologic findings in the gastrointestinal system are caused by this choleretic effect. METHODS: During the experimental procedures, animals at first were divided into 2 major groups of A and B; A consisted of the animals whose bile was not collected, and B consisted of animals whose bile was collected. Later, these 2 groups were divided into 4 subgroups consisting of 6 animals each. Sham operations were performed on the animals in group SH-A and SH-B. The animals in group saline-A and saline-B were given 0.9% of sodium chloride (isotonic sodium chloride). The animals in group LR-A and LR-B received lactated Ringer's solution. The last group (PEG-A and PEG-B) underwent WBI by using polyethylene glycol solution (PEG). After completing WBI, animals were rested for 4 hours, and at the end of resting time, laparotomy was performed to take biopsy specimens from stomach, small bowel, and large bowel. All of the specimens were evaluated and graded for congestion, edema, and inflammation by the individual blinded pathologist. RESULTS: According to the results, WBI has been shown to affect biliary secretion and to have a choleretic effect (P <.05, Tuckey-Kramer). The choleretic effect has also been shown to be responsible for histopathologic alterations in some groups (P <.05, Tuckey-Kramer). The most severe changes of congestion, edema, and inflammation have been detected in isotonic sodium chloride solutions in all groups. The least alterations have been seen in lactated Ringer's and PEG solutions. CONCLUSIONS: In light of these findings, it might be concluded that the use of WBI can cause different degrees of histopathologic changes in gastrointestinal system depending on the type of solutions. WBI has been shown to have choleretic effect, and it was found that there is a connection between histopathologic changes in gastrointestinal system and choleretic effect of WBI.

Clinical spectrum of muscle-eye-brain disease: from the typical presentation to severe autistic features.

Muscle-eye-brain disease (MEB) is an autosomal recessive congenital muscular dystrophy with ocular abnormalities and type II lissencephaly. MEB is caused by mutations in the protein O-linked mannose beta1,2-N-acetylglucosaminyltransferase (POMGnT1) gene on chromosome 1q33. POMGnT1 is a glycosylation enzyme that participates in the synthesis of O-mannosyl glycan. The disease is characterized by altered glycosylation of alpha-dystroglycan. The clinical spectrum of MEB phenotype and POMGnT1 mutations are significantly expanded. We would like to present two cases with MEB disease with POMGnT1 mutations, whose clinical picture shows heterogeneity. The patient with R442H mutation had the classical form of the disease although the one with IVS17-2A-->G homozygous mutation had severe autistic features as the dominating presenting sign. These two cases represent different spectrums of one disorder. To the best of our knowledge, autistic features and stereotypical movements have not been included thus far as a part of broad and heterogeneous MEB spectrum.

Beta-sarcoglycan gene mutations in Turkey.

The term limb-girdle muscular dystrophy (LGMD) refers to a group of muscular dystrophies that, at the outset, affect primarily the muscles of the hip and shoulder girdle. Limb-girdle muscular dystrophy is genetically heterogeneous comprising autosomal dominant (types LGMD 1A-1E) as well as autosomal recessive forms (types LGMD 2A-2J known). A subgroup among the autosomal recessive forms comprises the sarcoglycanopathies (LGMD2C-2F), caused by mutations in the gamma (gamma-SG), alpha (alpha-SG), beta (beta-SG) and delta (delta-SG) sarcoglycan genes, respectively. The sarcoglycans form the sarcoglycan complex, part of the dystrophin-associated glycoproteins. Mutations in the beta-SG gene causes LGMD2E. Disease severity, in this form, varies from mild to severe phenotypes depending on the individual mutation. Homozygous missense mutations in critical locations may result in the total absence of alpha-, beta- and gamma-sarcoglycan from the muscle membrane and a phenotype as severe as null mutations. In the present study, through screening 80 unrelated LGMD2 families, we identified 13 families with LGMD2E. Mutations in the beta-SG gene were identified in 12 patients from nine families. One of these patients carried a previously reported truncating mutation (Q11X), while the other 11 carried novel missense/rameshift mutations (M1L, V89M, I92T, I92S, 739insA), some of which were seen in more than one patient and may, therefore, be more common in the Turkish population.

FKRP gene mutations cause congenital muscular dystrophy, mental retardation, and cerebellar cysts.

BACKGROUND: Congenital muscular dystrophies (CMD) are autosomal recessive disorders that present within the first 6 months of life with hypotonia and a dystrophic muscle biopsy. CNS involvement is present in some forms. The fukutin-related protein gene (FKRP) is mutated in a severe form of CMD (MDC1C) and a milder limb girdle dystrophy (LGMD2I). Both forms have secondary deficiencies of laminin alpha2 and alpha-dystroglycan immunostaining. Structural brain involvement has not been observed in patients with FKRP gene mutations. METHODS: The authors studied two unrelated patients who had a pattern of muscle involvement identical to MDC1C, mental retardation, and cerebellar cysts on cranial MRI. The FKRP gene was analyzed along with the skeletal muscle expression of laminin alpha2 and alpha-dystroglycan. RESULTS: The muscle biopsy of both patients showed severe dystrophic findings, a reduction in laminin alpha2, and profound depletion of alpha-dystroglycan. Both patients had homozygous FKRP gene mutations not previously reported (C663A [Ser221Arg] and C981A [Pro315Thr]). CONCLUSIONS: Mutations within the FKRP gene can result in CMD associated with mental retardation and cerebellar cysts. This adds structural brain defects to the already wide spectrum of abnormalities caused by FKRP mutations. The severe depletion of alpha-dystroglycan expression suggests that FKRP is involved in the processing of alpha-dystroglycan.

Lamin A/C mutations with lipodystrophy, cardiac abnormalities, and muscular dystrophy.

Mutations in the lamin A/C gene are found in Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy with cardiac conduction disturbances, dilated cardiomyopathy with conduction system disease, and familial partial lipodystrophy. Cases with lamin A/C mutations presenting with lipodystrophy in combination with cardiac and/or skeletal muscle abnormalities are described.

Genetic identity of Marinesco-Sjögren/myoglobinuria and CCFDN syndromes.

OBJECTIVE AND BACKGROUND: To describe three Gypsy families with Marinesco-Sjögren syndrome (MSS), demyelinating neuropathy, and recurrent episodes of myoglobinuria in five of the six affected subjects. Because these families originated from the same genetically isolated founder population as did patients with congenital cataracts facial dysmorphism neuropathy (CCFDN) syndrome, and because the two syndromes have clinical manifestations in common, we hypothesized that the two related, albeit distinct, syndromes may represent clinical variants of a single genetic disorder. METHODS: Clinical studies were conducted and linkage and haplotype analyses were performed for the three families. A total of 16 individuals, including the 6 with MSS and 10 unaffected relatives, were genotyped for six polymorphic microsatellite markers from the CCFDN region on 18qter. RESULTS: Linkage analysis of markers in the 18qter region, where we previously had located the CCFDN gene, produced a lod score of 3.55, demonstrating colocalization of the gene responsible for MSS with demyelinating neuropathy and myoglobinuria with the CCFDN gene. Moreover, the patients with MSS shared the conserved marker haplotype found in CCFDN chromosomes. CONCLUSIONS: These data suggest that Marinesco-Sjögren syndrome with peripheral neuropathy and myoglobinuria, and congenital cataracts facial dysmorphism neuropathy syndrome are genetically identical and are caused by a single founder mutation.

Spinal muscular atrophy with progressive myoclonic epilepsy: report of new cases and review of the literature.

Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterised by loss of motor function and muscle atrophy due to anterior horn cell degeneration. The most common variant is chromosome 5-linked proximal SMA, ranging in severity from congenital onset and infantile death to onset in adult life. Genetically separate variants with different distribution of weakness and/or additional features such as central nervous system involvement have been described. A rare variant with associated myoclonic epilepsy and lower motor neuron disease had been previously described in three families before the SMN gene, responsible for the common form of SMA, was isolated. We report four patients from two additional families affected by a syndrome characterised by severe and progressive myoclonic epilepsy and proximal weakness, tremor and lower motor neuron disease proven by electrophysiologic and muscle biopsy findings. Extensive metabolic investigations were normal and genetic analysis excluded the SMN gene. This study confirms that the association of myoclonic epilepsy and motor neuron disease represents a separate clinical and genetic entity from chromosome 5-linked SMA, the primary defect of which remains unknown.

Muscular dystrophy and neuronal migration disorder caused by mutations in a glycosyltransferase, POMGnT1.

Muscle-eye-brain disease (MEB) is an autosomal recessive disorder characterized by congenital muscular dystrophy, ocular abnormalities, and lissencephaly. Mammalian O-mannosyl glycosylation is a rare type of protein modification that is observed in a limited number of glycoproteins of brain, nerve, and skeletal muscle. Here we isolated a human cDNA for protein O-mannose beta-1,2-N-acetylglucosaminyltransferase (POMGnT1), which participates in O-mannosyl glycan synthesis. We also identified six independent mutations of the POMGnT1 gene in six patients with MEB. Expression of most frequent mutation revealed a great loss of the enzymatic activity. These findings suggest that interference in O-mannosyl glycosylation is a new pathomechanism for muscular dystrophy as well as neuronal migration disorder.

Clinical and genetic distinction between Walker-Warburg syndrome and muscle-eye-brain disease.

BACKGROUND: Three rare autosomal recessive disorders share the combination of congenital muscular dystrophy and brain malformations including a neuronal migration defect: muscle-eye-brain disease (MEB), Walker-Warburg syndrome (WWS), and Fukuyama congenital muscular dystrophy (FCMD). In addition, ocular abnormalities are a constant feature in MEB and WWS. Lack of consistent ocular abnormalities in FCMD has allowed a clear clinical demarcation of this syndrome, whereas the phenotypic distinction between MEB and WWS has remained controversial. The MEB gene is located on chromosome 1p32-p34. OBJECTIVES: To establish distinguishing diagnostic criteria for MEB and WWS and to determine whether MEB and WWS are allelic disorders. METHODS: The authors undertook clinical characterization followed by linkage analysis in 19 MEB/WWS families with 29 affected individuals. With use of clinical diagnostic criteria based on Finnish patients with MEB, each patient was categorized as having either MEB or WWS. A linkage and haplotype analysis using 10 markers spanning the MEB locus was performed on the entire family resource. RESULTS: Patients in 11 families were classified as having MEB and in 8 families as WWS. Strong evidence in favor of genetic heterogeneity was obtained in the 19 families. There was evidence for linkage to 1p32-p34 in all but 1 of the 11 pedigrees segregating the MEB phenotype. In contrast, linkage to the MEB locus was excluded in seven of eight of the WWS families. CONCLUSION: These results allow the classification of MEB and WWS as distinct disorders on both clinical and genetic grounds and provide a basis for the mapping of the WWS gene(s).

MR imaging of pelvic and thigh muscles in congenital muscular dystrophy.

To define and compare the magnetic resonance (MR) imaging findings of pelvic and thigh muscles in merosin-deficient and merosin-positive congenital muscular dystrophy, 10 patients with merosin-positive and six patients with merosin-deficient muscular dystrophy were examined in a 0.5 T MR imaging unit. Intensity and atrophy scores were given to individual muscles by two radiologists and were calculated for three muscle groups (pelvic, anterior thigh and posterior thigh muscles). Rectus femoris was affected less than the vastus muscles in 40 percent of cases in merosin-positive patients, whereas there was no selective sparing in merosin-deficient patients. Sartorius and gracilis were relatively spared in both groups. The most consistently affected muscles were gluteus maximus, adductor magnus and brevis in merosin-positive patients. Atrophy was more prominent in the adductor muscles in the merosin-deficient group. Intensity scores of anterior thigh muscles of the merosin-positive group were significantly higher than those of the merosin-deficient group (U = 8, p = 0.016). When stepwise logistic regression model was applied, intensity score of the anterior thigh muscles was found to be the best differentiating variable. The regression analysis model formed was able to differentiate the two forms with a sensitivity of 80 percent and specificity of 83 percent.