Congenital nephrotic syndrome: a novel phenotype of type I carbohydrate-deficient glycoprotein syndrome

Type I carbohydrate-deficient glycoprotein (CDG) syndrome is a genetic multisystem disorder generally without overt renal problems. We report a neonate with neurological abnormalities and congenital nephrotic syndrome of diffuse mesangial sclerosis type. Serum transferrin isoelectric focusing showed the typical abnormalities of type I CDG syndrome. Normal transferrin focusing findings in other patients with similar renal problems excluded the possibility of a secondary biochemical phenomenon. The diagnosis of type I CDG syndrome was confirmed by demonstration of a deficiency of phosphomannomutase. No evidence of pontocerebellar atrophy was found in imaging or at autopsy. We conclude that congenital nephrotic syndrome may occur in type I CDG syndrome, and that this diagnosis should be considered in patients with congenital nephrotic syndrome. Absence of pontocerebellar atrophy does not exclude the diagnosis of type I CDG syndrome.     

MR findings in pontocerebellar hypoplasia

We present four cases with combined hypoplasia of the cerebellum and the ventral pons-pontocerebellar hypoplasia (PCH). PCH represents an autosomal recessive neurodegenerative disorder with fetal onset. The disease is rare, with less than 20 cases having been reported. The main findings of PCH and the inclusion criteria for our cases can be summarised as progressive microcephaly from birth, pontocerebellar hypoplasia documented by MRI and marked chorea, which may change, later in childhood, to more dystonic patterns. The cerebral cortex becomes progressively atrophic. Motor and mental development are delayed, and epilepsy, mainly tonic-clonic seizures, is frequent. The MRI features in all of our cases were: (1) Hypoplastic cerebellum situated close to the tentorium. The hypoplastic cerebellum has a reduced number of folia, in contrast to the normal number of thin folia in simple cerebellar atrophy. (2) The cerebellar hemispheres are reduced to bean-like or wing-like structures. The cerebellar hemispheres appear to 'float' in the posterior fossa. (3) Markedly hypoplastic ventral pons. (4) Slight atrophy of the supratentorial gyral pattern. (5) Dilated cerebromedullary cistern and fourth ventricle. (6) Delayed myelination of the white matter. (7) No significant disorganisation of brain architecture and no severe corpus callosum defect.     

Adult-onset hereditary ataxia in Scotland

A systematic search for cases of adult-onset hereditary ataxia was conducted on location in Scotland. The investigation resulted in the discovery of eight pedigrees with 42 patients of whom 16 were alive in 1975. Nine patients were examined by the authors and recent hospital records were available on the remaining seven. The clinical features were quite variable. In declining order of frequency, findings were gait and limb ataxia, dysarthria, hyperreflexia, extrapyramidal motor disturbances, impaired vibratory sense, spasticity, defects of extraocular movements and nystagmus, reflex depression, Babinski signs, impaired joint position sense, muscle weakness, optic atrophy, and mental abnormalities. Foot deformity occurred only once. Inheritance was compatible with autosomal dominant transmission, but complicated by consanguinity in two families. The minimum prevalence was calculated as 0.31/100,000. Autopsy in two members in one family revealed olivopontocerebellar degeneration.     

Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations

We report clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with 4 different missense point mutations in exons 2, 4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene, that result in amino acid substitutions of histidine46 by arginine (H46R), leucine84 by valine (L84V), isoleucine104 by phenylalanine (I104F), and valine148 by isoleucine (V148I), in 5 Japanese families. Although features of progressive neurogenic muscular atrophy were common in patients of these families, patients of each family showed characteristic clinical features. FALS patients with the H46R mutation showed a benign clinical course and stereotype progression of muscular weakness and atrophy beginning from the legs. In FALS with the L84V mutation, while the clinical course of the disease was similar, the age at onset was younger in men than women. The patients with I104F showed wide ranges of age at onset and duration with ophthalmoparesis and sensory involvement in one patient. Those with the V148I mutation showed younger age at onset and variable first symptoms within the family. Although lower motor sign was evident in all cases, hyperreflexia varied from 0 to 100% among patients with the different mutations, and the Babinski sign was not observed in any case. Bulbar palsy was frequent with I104F, but not with H46R. SOD activity of the red blood cells was severely reduced with I104F and V148I, but was slightly reduced with H46R. These results suggest that familial ALS with different mutations of the Cu/Zn SOD gene each showed clinical characteristics, and that genetic mutations and clinical features are well correlated in familial ALS.     

Does the ataxo-choreic form of DRPLA exist in Europe? Search of mutation in 120 families

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by a degeneration of cerebellar and pallidal efferents, more frequent in Japan. Isolated cases are also encountered. Patients present with variable combination of signs including myoclonus, ataxia, epilepsy, choreoathetosis and dementia, with onset from childhood to the seventh decade. Clinically, DRPLA may be undistinguishable from other genetic disorders, in particular Huntington's disease or the spinocerebellar ataxias. The genetic basis of the inherited form of DRPLA is an expansion to more than 49 repeats of an unstable trinucleotide (CAG) in the DRPLA gene on the short arm of chromosome 12. We determined the frequency of this mutation in patients with the DRPLA phenotype. One hundred and seventeen patients with cerebellar ataxia, from 94 families and 23 isolated cases, as well as 3 patients from families with undiagnosed autosomal dominant neurodegenerative disorders were investigated for the presence of the expanded sequence. None of the patients carried this mutation. This finding suggests that DRPLA is rare in the French population. The search for the DRPLA mutation is justified in patients with the DRPLA phenotype, however, since genetic counselling is often requested and neither clinical, nor neuropathological examinations permit a definite diagnosis of the underlying disease.     

The 1993 epidemic of dengue fever in Mangalore, Karnataka state, India

Distal spinal muscular atrophy is a rare lower motor neuron disorder that may be difficult to distinguish clinically from type II Charcot-Marie-Tooth disease. We report on clinical and pathologic findings in 13 members of a four-generation extended family with autosomal dominant distal spinal muscular atrophy. The patients developed a slowly progressive lower motor neuron disorder involving mainly the distal lower extremities; onset was from the second to fourth decades. Electromyography and muscle biopsy findings were indicative of motor denervation. Combined silver/cholinesterase/immunocytochemical staining of intramuscular nerve revealed abundant collateral axonal branching in mild disease but marked loss of terminal motor endplate innervation in the more severe state, suggesting decreased growth of motor axon collaterals with disease progression. Multipoint DNA linkage analysis showed that this family's disorder is not linked to the chromosome 5q11.2-13.3 spinal muscular atrophy locus.     

Charcot-Marie-Tooth disease. Clinical study in 45 patients

Charcot-Marie-Tooth (CMT) disease is the commonest inherited peripheral neuropathy. The clinical study of 45 patients with CMT is presented. They were derived from Antonio Pedro Hospital of Universidade Federal Fluminense in Niteroi, RJ, Brazil. Such patients could be divided by the motor conduction velocity in two types: a demyelinating form or type I (11 cases) and an axonal form or type II (34 cases). The disease was inherited as an autosomal dominant trait in 23 patients and as an autosomal recessive trait in 7 cases. In 15 patients the disorder was sporadic. The age of onset was in most of our cases before the 20 years. All of them had distal weakness in lower limbs. 38.2% had also distal weakness in upper limbs. 80% had distal wasting of the lower limbs and 50% had distal wasting of upper limbs. The tendon reflexes were absent in 64% in lower limbs and in 28% in upper limbs. The sensitive impairment in the distal regions of the extremities was mild in most patients. We found enlargement of peripheral nerves in 7 patients of type I. Pes cavus was present in 21 cases and scoliosis in 7. We found postural tremor of hands in 6 patients. In 9 cases there were rare features as mental retardation, trigeminal nevralgia, optic atrophy, deafness and calf enlargement. In most of our cases the clinical course was very slow progressive. A greater severity was seen in our sporadic cases.     

Intralesionally implanted cisplatin plus systemic carmustine for the treatment of brain tumor in rats

Early alexia and higher visual impairments characterize Posterior cortical atrophy (PCA), a progressive dementing syndrome most often caused by Alzheimer disease. Posterior cortical atrophy is rare, and the nature of the visual impairments in PCA are unclear. The authors observed two patients who had an insidiously progressive reading difficulty characterized by letter-by-letter reading and otherwise intact cognitive functions. Over time, these patients developed "ventral simultanagnosia" with preserved detection of multiple stimuli but inability to interpret whole scenes. Subsequently, they progressed to Balint syndrome with "dorsal simultanagnosia," optic ataxia, and oculomotor apraxia. Structural imaging was normal, but functional imaging revealed posterior cortical dysfunction. On a letter reading task, both patients had a word superiority effect, and on a whole word reading task, they could not read most words with missing or crosshatched letters. An inability to assess whole scenes progressed to an inability to detect more than one stimulus in an array. These findings suggest an evolution of PCA with progressive difficulty in visual integration beginning with letters, progressing to whole scenes, and culminating in Balint syndrome. These changes may reflect an extension of the pathophysiology of PCA from the extrastriate visual cortex to its occipitotemporal and occipitoparietal connections.     

A family with a syndrome of ectopia lentis, spontaneous filtering blebs, and craniofacial dysmorphism

Six members of a family presented with a syndrome of mild facial dysmorphism, subluxation of the crystalline lenses, variable degrees of angle closure by iridocorneal adhesions, and patchy areas of iris atrophy. Three nonoperated eyes of two patients had spontaneous filtering blebs that presented as avascular cystic elevations of the superior conjunctiva. Systemic workup of all patients was negative for evidence of diseases known to be associated with dislocated lenses. The pedigree is most compatible with autosomal recessive inheritance with pseudodominance.     

Ponto-cerebellar hypoplasia with dystonia: clinico-pathological findings in a sporadic case

Microcephaly, absent psychomotor development and dystonic limb movements were the main clinical features of a 3-year-old girl affected by hypoplasia of the pontocerebellar structures. As in the few previously reported cases there are discrepancies between the severity of lesions in the supratentorial and infratentorial compartments. Pathological features such as size reduction of the ventral pons, inferior olive atrophy, dentate nucleus fragmentation, and thinning of the cerebellar cortex suggest an impaired maturation of the involved structures due to a prenatal condition (dated at about 20-28 weeks of gestation). Somatotopic analysis failed to provide conclusive evidence on the primary target of the disease. The affected structures originate from the dorsal rhombencephalic region at about the same gestational age, and their maturation is probably under the control of sets of genes which regulate pattern formation. Early abnormal functioning of such genes might lead to the selected morphogenetical alterations observed in ponto-cerebellar hypoplasia. The normal morphogenetic pattern of the supratentorial structures and the mild lesions observed suggest that their late involvement can be related to a different pathogenetic process.     

A pedigree of autosomal dominant limb-girdle myopathy with rimmed vacuole formation

We describe a kindred with autosomal dominant myopathy with preferential proximal limb muscle involvement. This disorder is characterized clinically by early adult onset, slow progression, normal life expectancy, weakness and atrophy of proximal limb muscles, especially in the lower limbs. Laboratory examinations showed myopathic changes mixed with neuropathic components on needle electromyography, slight elevation of serum creatine kinase, and absent cardiac involvement. In biopsied muscle findings of two patients, the presence of rimmed vacuoles was the most striking finding to explain muscle degeneration, though a few necrotic fibers were present. The pathologic and clinical findings in the present family are almost similar to those seen in "adult-onset autosomal dominant limb-girdle muscular dystrophy" reported by Chutkow et al.     

Clinical picture and therapy of hypertrophic cardiomyopathy

Although central vision in Stargardt's disease is impaired relatively early, peripheral function is usually little affected and patients do not lose all vision. We report 4 patients with bull's-eye macular dystrophy that is indistinguishable from Stargardt's disease/fundus flavimaculatus, but with very depressed peripheral retinal function. One patient had bull's-eye maculopathy with a dark choroid on the fluorescein angiogram with a normal peripheral fundus and good retinal function initially. Sixteen years later, however, peripheral bone corpuscle pigmentation and optic disc atrophy developed and the electroretinogram became nonrecordable. Three patients from another family also had peripheral pigment degeneration besides macular degeneration. These cases may represent a rare combination of Stargardt's disease and retinitis pigmentosa. However, there was no clinical sign or even suggestion of retinitis pigmentosa at the initial examination in 1 patient. The mode of inheritance in 3 of our patients is probably autosomal recessive.     

Autosomal recessive microcephaly, microcornea, congenital cataract, mental retardation, optic atrophy, and hypogenitalism. Micro syndrome

Three affected children from an inbred family had microcornea, microcephaly, congenital cataract, severe mental retardation, retinal dystrophy, optic nerve atrophy, hypothalamic hypogenitalism, and agenesis of the corpus callosum. The disorder is presumably autosomal recessive; no identical syndrome has been described, but we consider syndromes with similar features.     

Progressive juvenile segmental spinal muscular atrophy

Juvenile segmental spinal muscular atrophy (JSSMA) typically involves the distal upper extremities and follows a benign course over 2-4 years then stabilizes. We report 2 males who presented in their teens with insidious distal upper extremity atrophy and weakness as in typical JSSMA but who then progressed to involvement of the lower extremities and hyperreflexia. There was no sensory loss. Electromyography and muscle biopsy demonstrated features consistent with localized anterior horn cell dysfunction. These patients are noteworthy because they demonstrate that some patients with JSSMA also may have involvement of the lower limbs several years after initial presentation. Progressive JSSMA may be categorized in the clinical spectrum between the spinal muscular atrophies and amyotrophic lateral sclerosis.     

Dual projection from the medial septum to the supramammillary nucleus in the rat

Hereditary inclusion body myopathies comprise autosomal recessive and autosomal dominant muscle disorders that have a variable clinical phenotype but share similar morphological features. These include rimmed vacuoles within muscle fibres and collections of intrasarcoplasmic and intranuclear tubulofilamentous inclusions, 16-18 nm in external diameter. The resemblances and the differences between the sporadic and the hereditary inclusion body myopathies are discussed. Recent advances in the identification of various proteins involved in these diseases are mentioned because they have provided better insight into their underlying pathophysiological mechanisms. Linkage studies have allowed the localization of the genetic defect of some hereditary inclusion body myopathies and related disorders, contributing to their individualization.     

High levels of HCB and DDE associated with reproductive failure in prairie falcons (Falco mexicanus) from California

With the evidence of deletions in the region responsible for autosomal recessive spinal muscular atrophy (SMA) on chromosome 5, it is now possible to further clarify the clinical and diagnostic findings in proximal SMA. Homozygous deletions of the survival motor neuron (SMN) gene can be detected in about 95% of patients with early onset SMA. In a series of more than 200 patients, we tested 31 patients with atypical features of SMA who fulfilled at least one exclusion criterion according to the diagnostic criteria of the International SMA Consortium for the presence of SMN gene deletions. The patients were subdivided into two groups: 1. Seven index patients being not deleted for the SMN gene who belonged to a well-defined SMA plus variant that has already been shown to be unlinked with chromosome 5q markers: diaphragmatic SMA, SMA plus olivopontocerebellar hypoplasia, SMA with congenital arthrogryposis and bone fractures. 2. Twenty-four patients with clinical signs of SMA and neurogenic findings in EMG/muscle biopsy who had unusual features or other organ involvement. In order to structure this heterogeneous group, each patient was assigned to a subgroup according to the leading atypical feature. In 5 out of 8 unrelated patients with a history of preterm birth and/or perinatal asphyxia leading to a picture of severe SMA in combination with respiratory distress and/or cerebral palsy, no deletion of the SMN gene could be detected. There were five unrelated patients with extended central nervous system involvement (cerebral atrophy, EEG abnormalities, pyramidal tract signs, evidence of cerebellar involvement). Most of these patients (4/5) proved to belong to SMA 5q on the basis of SMN gene deletion findings. The same applied to a group of three patients with classical SMA in association with congenital malformations (mainly heart defect). A fourth group of three patients was characterized mainly by an unusual improvement of the condition; in these patients no SMN gene deletions were present. In three index patients a more complex syndrome of the CNS and other organs was suggested, but the detection of SMN gene deletions in two of them made a coincidence of features more likely. In addition, SMN gene deletions were found in two patients with evidence of congenital fibre type dysproportion in one and extremely raised CK activity ( > 10fold) in the other. While the confirmation of SMN gene deletions is very useful in cases with diagnostic doubts, caution is required when offering prenatal prediction with regard to SMA 5q in families with atypical features. There is strong evidence that there are clinical entities resembling SMA which most likely have another pathogenetic background.     

The wide spectrum of myofibrillar myopathy suggests a multifactorial etiology and pathogenesis

BACKGROUND: Myofibrillar myopathy (MFM) is characterized by nonhyaline lesions (foci of myofibrillar destruction) and hyaline lesions (cytoplasmic inclusions composed of compacted myofibrillar residues) on light and electron microscopy. Immunocytochemistry demonstrates the abnormal expression of desmin and numerous other proteins. The clinical, laboratory, and histologic features of MFM are heterogeneous, making a diagnosis difficult. RESULTS: We diagnosed eight patients with MFM over the preceding 3 years. MFM was inherited in an autosomal dominant pattern in one patient, developed sporadically in five patients, and was induced by an experimental chemotherapy, Elinafide (Knoll, Parsippany, NJ), in two patients. Age at onset ranged from 14 to 64 years. The pattern of weakness was variable but involved proximal and distal muscles. Five patients had evidence of a cardiomyopathy. Electromyography demonstrated muscle membrane instability and small, polyphasic motor unit potentials. Serum creatine kinase levels were normal to moderately elevated (<10x normal). Light and electron microscopy demonstrated the characteristic pattern of nonhyaline and hyaline lesions and the associated abnormalities on immunocytochemistry. CONCLUSIONS: Patients demonstrate a wide spectrum of clinical, laboratory, and histologic abnormalities. Chemotherapy-induced MFM has abnormalities on immunocytochemistry similar to the those of hereditary and sporadic cases. The pathogenesis of MFM is likely heterogeneous. However, MFM is distinctive in that it can preferentially affect distal muscles and has a frequent association with cardiomyopathy. The cardiomyopathy may be amenable to treatment with pacemaker insertion or cardiac transplantation.     

Hereditary tubulo-interstitial nephropathy

Most of the hereditary tubulointerstitial nephropathy see the cyst formation in the kidney. Among them, juvenile nephronophthisis and medullary sponge kidney, which primarily involve the tubule structures of the renal medulla, are associated with variable enlargement of the distal tubules and collecting ducts and with interstitial fibrosis and inflammation of a variable extent. Juvenile nephronophthisis features sodium wasting, anemia, and renal failure. Eighty % of juvenile nephronophthisis is an autosomal recessive disorder, and it also has a variant form which is an autosomal dominant disease. A gene for autosomal recessive juvenile nephronophthisis is now mapped to 2q13, although no linkage has been observed in autosomal dominant variant to this region. Thus genetic heterogeneity between autosomal recessive variant and autosomal dominant variant of juvenile nephronophthisis is suggested. Juvenile nephronophthisis progress to end-stage renal failure. In contrast, medullary sponge kidney, which features nephrocalcinosis and urinary stones, is a relatively benign condition and occurs occasionally in the same family.     

Unilateral spatial neglect in degenerative brain pathology.

Objective: In an attempt to interpret neglect as a disconnection syndrome, it is currently proposed that the disorder results from disorganization of large-scale networks involved in attentional spatial processes rather than of individual brain areas. We hypothesize that as degenerative brain diseases are “system pathologies,” degeneration could be restricted to some of the neural subsystems implicated in the functional organization of spatial attention and different neglect syndromes could emerge depending on the patterns of the subsystems involved. Method: We studied five neglect patients: one with corticobasal degeneration (CBD), three with Posterior Cortical Atrophy (PCA) and one with frontotemporal dementia (FTD). Results: The patient with CBD and left parietoccipital atrophy showed right allocentric neglect; the three patients with PCA mostly distributed in the right posterior regions showed left egocentric extrapersonal neglect; the patient with FTD, who displayed more severe frontotemporal atrophy on the right, had left motor-executive neglect for both personal and extrapersonal space. All patients also presented a deep breakdown of spatial working memory. Conclusion: Our data would confirm that left neglect is more frequent than right neglect also in degenerative pathology and that damage to different neural substrates can produce different types of neglect. Our findings are also consistent with the hypothesis that both lateralized and nonlateralized attention disorders contribute to generate the syndrome. We suggest that evidence from degenerative diseases may contribute to construction of models of spatial attention. (PsycINFO Database Record (c) 2011 APA, all rights reserved)