Presymptomatic diagnosis of spinal muscular atrophy (SMA) III confirmed by deletion analysis of the survival motor neuron gene.
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Child↗
Biomedical subjects
E Bertini
Publications and source records attributed to E Bertini.
Remission in dihydroxyphenylalanine-responsive dystonia.
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Child↗
Interferon-alpha may benefit steroid unresponsive chronic inflammatory demyelinating polyneuropathy.
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Adult↗
Autosomal recessive hypermyelinating neuropathy.
We studied three patients from two kinships, affected by early onset hereditary motor and sensory neuropathy with probable autosomal recessive inheritance (HMSN type III). Morphological studies of sural nerve biopsies revealed an abnormal myelin proliferation. Two adult patients with long-term follow up, lost ability to walk at 28 and 22 years and showed severe involvement of the cranial nerves. Our observations suggest that "hypermyelination neuropathy" with early onset is a progressive disease with poor long-term prognosis. In one kinship the occurrence of the disease in two sibs of both sexes but not in parents, is consistent with an autosomal recessive inheritance. Familial cases of hypermyelination neuropathy have not been described in previous reports. Morphological aspects of this condition are compared with other forms of hypermyelination neuropathy.
Adult↗
Reducing body myopathy and desmin storage in skeletal muscle: morphological and biochemical findings.
We describe clinical, morphological and biochemical findings of a patient with reducing body myopathy (RBM). This 15-year-old patient was affected by severe limb-girdle progressive myopathy with asymmetric distribution. Muscle biopsy showed many fibers with cytoplasmic polymorphic masses, which stained dark purple with modified Gomori's trichrome, associated with proliferation of cytoplasmic bodies. Cytoplasmic polymorphic masses showed marked reducing activity with menadione-nitro blue tetrazolium reaction. Ultrastructurally, there was great amount of highly electron-dense tubular-filamentous structures of 16-17 nm in diameter. Immunohistochemistry showed that many fibers were positive for desmin. Sodium dodecyl sulfate-electrophoresis disclosed an increase in two bands of approximately 53 and 70 kDa, and Western blot demonstrated that the 53-kDa band was desmin. It was not possible to characterize the 70-kDa protein further.
Adolescent↗
A new syndrome with ethylmalonic aciduria and normal fatty acid oxidation in fibroblasts.
We describe four Italian male infants with a novel clinical phenotype characterized by orthostatic acrocyanosis, relapsing petechiae, chronic diarrhea, progressive pyramidal signs, mental retardation, and brain magnetic resonance imaging abnormalities. The first symptoms appeared after the termination of breast-feeding and introduction of formula feeding. Marked persistent 2-ethylmalonic aciduria was associated with abnormal excretion of C4-C5(n-butyryl-, isobutyryl-, isovaleryl-, and 2-methylbutyryl-)acylglycines and acylcarnitines and with intermittent lactic acidosis. Short- and branched-chain plasma acylcarnitine levels were also elevated. 2-Ethylmalonic aciduria is generally regarded as being indicative of a defect in fatty acid oxidation. Extensive studies of cultured fibroblasts failed to reveal such a defect. The observation of intermittent urinary excretion of 2-ethylhydracrylic acid pointed to involvement of the isoleucine R pathway in ethylmalonate biosynthesis. This hypothesis was tentatively corroborated by the biochemical responses to an oral isoleucine challenge in two patients. However, fibroblast studies showed normal oxidation rates of (14C)isoleucine (ul), indicating that this is not a defect of isoleucine oxidation expressed in skin fibroblasts. In one of two patients tested, cytochrome c oxidase activity was partially reduced (45%) in cultured fibroblasts. This unique clinical and biochemical phenotype identifies a new metabolic encephalopathy of yet undetermined cause.
Acyl-CoA Dehydrogenase↗
Bilateral, reversible, selective thalamic involvement demonstrated by brain MR and acute severe neurological dysfunction with favorable outcome.
We report on two children who presented acute, severe, neurological dysfunction with bilateral, reversible, selective thalamic lesions demonstrated by brain MRI. In both children neurological symptoms appeared two weeks after a febrile respiratory illness. Clinical conditions worsened in a few days to a stuporous state and tetraplegia in one and to coma with decerebrate posturing in the other. Three weeks after the onset, both children improved and recovered within one month. During the acute phase, brain MRI showed in both children bilateral hyperintense areas on T2-weighted sequences limited to both thalamic regions. During the follow-up, repeated brain MRI showed complete disappearance of abnormalities in one patient and a small residual left thalamic lesion in the other. In both patients hematological routine exams were normal. Bacterial and viral studies of serum and CSF were negative. CSF findings showed elevated white blood cell count and protein levels, with no oligoclonal IgG bands. Urine and CSF organic acids by GC/MS and plasma as well as CSF amino acids were normal. We believe that the benign evolution of this disorder and CSF findings strongly suggest a postinfectious process of the central nervous system.
Child, Preschool↗
High dose immunoglobulin IV treatment in adrenoleukodystrophy.
X-linked adrenoleukodystrophy (ALD) is an inborn error of peroxisomal metabolism characterised by progressive demyelination of the central nervous system and by hypoadrenalism. The biochemical defect of ALD results in an impairment in degradation of very long chain fatty acids (VLCFA) with their accumulation in plasma and tissues. Many therapeutic approaches have been tried. Recently, a restricted diet and glycerol trioleate/erucic (GTOE) supplementation have shown normalisation of VLCFA plasma levels, although they are not effective in altering the clinical course of X-linked ALD. The preliminary results are presented of a twelve month trial of immunomodulation by intravenous high-dose immunoglobulins in six patients, mean (SD) age 10.48 (2.8) affected by X-linked ALD, on VLCFA restricted diet plus GTOE supplementation therapy. Six patients aged 9.30 (1.5) with similar clinical characteristics and on the same restricted VLCFA regime of GTO/GTE therapy were studied as the control group. After two months VLCFA levels fell to normal values and remained so for all patients throughout the study. These data show that immunoglobulins are not able to arrest the progression of the disease. The MRI and clinical symptoms deteriorated to the same extent in both groups.
Adolescent↗
Hereditary metabolic cardiomyopathies.
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Cardiomyopathy, Dilated↗
Presymptomatic diagnosis of SMA III by genotype analysis.
Linkage analysis and prenatal prediction in families segregating autosomal recessive spinal muscular atrophy (SMA) has become feasible since the assignment of the locus responsible for type I-III SMA to region 5q12-q13.3. We have performed a segregation study of SMA in Italian families using molecular probes and highly informative PCR-based polymorphic markers. In one family, a 7-year-old boy affected with type III SMA and an 8-year-old apparently healthy brother had identical haplotypes. These findings prompted us to reexamine the apparently unaffected child. His neurological exam was normal. However, the electromyography (EMG) showed a pattern consistent with chronic SMA. To our knowledge this is the first example of presymptomatic diagnosis of SMA based on genotype analysis.
Base Sequence↗
Myopathy and hypertrophic cardiomyopathy with selective lysis of thick filaments.
We present a undescribed condition in a girl who died at 8 years of hypertrophic cardiomyopathy. Muscle and endomyocardial biopsies disclosed a selective loss of thick filaments ultrastructurally. In muscle biopsy histochemical abnormalities of myofibrillar AT-Pase were confined to type 1 fibres. Gel electrophoresis of muscle homogenate showed no qualitative abnormalities of slow and fast myosin heavy chains (MHC) and light chains, and the amount of the different myosin isozymes was in agreement with histochemical myofibrillar ATPase findings. The pathogenetic mechanisms have not been elucidated in this case but we suspect an abnormality of the beta-cardiac MHC gene, the only gene expressed in the heart and in type 1 skeletal muscle fibres.
Calmodulin-Binding Proteins↗
Manifesting heterozygotes in McArdle's disease: clinical, morphological and biochemical studies in a family.
We report a family with McArdle's disease with several affected individuals in two generations. This unusual pedigree for an autosomal recessive disease is explained by the existence of manifesting heterozygotes in the maternal line. The presence of symptoms in heterozygotes seems to be due to a decrease in myophosphorylase activity below a critical threshold, ranging between 30% and 45% of normal mean value. The occurrence of several manifesting heterozygotes in the maternal line only can be explained by compound heterozygosity of a defective allele and a pseudodeficient allele for myophosphorylase, or by a genetic factor which regulates the phenotypic expression of the gene.
Adolescent↗
Cardiomyopathy may be the only clinical manifestation in female carriers of Duchenne muscular dystrophy.
Cardiomyopathy was reported in a few Duchenne muscular dystrophy (DMD) carriers with clinical evidence of myopathy. We report two carriers with dilated cardiomyopathy, increased serum CK, and no symptoms of muscle weakness. In heart biopsies of both patients, dystrophin-the protein product of DMD locus--was absent in many fibers. Dilated cardiomyopathy may be the only manifestation of dystrophin gene mutation in carriers.
Adult↗
Giant axonal neuropathy: report on a case with focal fiber loss.
We report on a 5 1/2 year-old boy with chronic progressive polyneuropathy, ataxia, and pyramidal signs. His hair was not curled. Sural nerve biopsy disclosed many axons enlarged by accumulation of 10-nm neurofilaments and a marked variability in the number of myelinated fibers as well as in the amount of axonal enlargements among different fascicles. These findings and the electrophysiological data were consistent with a giant axonal polyneuropathy with a multifocal fiber loss.
Axons↗
Peripheral sensory-motor polyneuropathy, pigmentary retinopathy, and fatal cardiomyopathy in long-chain 3-hydroxy-acyl-CoA dehydrogenase deficiency.
An 11-month-old girl presented acute episodes of hypoglycaemia and hepatic encephalopathy reminiscent of Reye syndrome and 3-hydroxydicarboxylic aciduria. The patient showed peculiar clinical manifestations of severe sensory-motor neuropathy, pigmentary retinopathy, and cardiomyopathy. She died of cardiac failure. Pathological studies of peripheral nerve showed signs of axonal neuropathy and demyelination. Enzymatic studies in cultured fibroblasts showed a deficiency of mitochondrial long-chain 3-hydroxyacyl-CoA-dehydrogenase. Peripheral nerve involvement and retinal pigmentary degeneration have as yet not been described in patients with proven defects of mitochondrial beta-oxidation.
3-Hydroxyacyl CoA Dehydrogenases↗
Biopsy diagnosis of a case of adult onset orthochromatic leukodystrophy. Clinical and brain biopsy findings.
We report the intra vitam histopathological findings on the brain of a female patient presenting an adult form of orthochromatic leukodystrophy. At 38 years of age the patient began to show progressive dementia and a pseudobulbar syndrome. The pedigree revealed an autosomal dominant pattern of inheritance. The CT scan showed a wide hypodensity of the anterior white matter. Biochemical investigations showed only a slight elevation of serum VLCFA and no alteration of urinary enzymatic activities. Cortical and subcortical biopsy specimens from the right frontal lobe showed: neuronal loss in the gray matter, accumulation of autofluorescent material within residual neurons and sudanophilic material within macrophages and astrocytes, sparing of axons. Electron microscopy showed lamination and fragmentation of the myelin and the presence of electrondense bodies and vesicular material into oligodendrocytes and astrocytes. We discuss the differential diagnosis of OLD forms with adult onset, namely between Löwenberg-Hill disease and the pure form of OLD with pigmented glial cells.
Biopsy↗
Peripheral neuropathy with giant axons and cardiomyopathy associated with desmin type intermediate filaments in skeletal muscle.
A sporadic case (female, aged 14 years) is reported who was affected by myopathy, restrictive cardiomyopathy and sensory motor polyneuropathy. A muscle biopsy showed accumulation of osmiophilic granular and filamentous material on electron microscopy, which stained positively in immunofluorescence for desmin. Increased desmin phosphorylated isoforms have been demonstrated by one- and two-dimensional electrophoresis. Sural nerve biopsy showed a peripheral neuropathy with giant axons, filled with closely packed neurofilaments. Clinical and morphological aspects of this new disease entity are discussed with regards to the classical form of giant axonal neuropathy and to other conditions of peripheral neuropathy with giant axons.
Adolescent↗
Fatal infantile liver failure associated with mitochondrial DNA depletion.
A 3-month-old girl was admitted to the hospital because of hypotonia and frequent vomiting. She had severe metabolic acidosis and her liver function was abnormal. Hepatomegaly and rapidly progressive liver failure developed, and she died at 4 months of age. Two half-siblings from a different mother had died in infancy of an undiagnosed myopathy. The liver was fatty and hepatocytes were filled with large and small lipid droplets. Other tissues were morphologically normal. The respiratory chain enzymes containing subunits encoded by mitochondrial DNA were markedly decreased in liver, partially decreased in muscle, but normal in other tissues. Southern blot analysis showed 90% depletion of mitochondrial DNA in liver, 53% depletion in muscle, and normal amounts in other tissues. This is the second case of fatal infantile liver failure associated with mitochondrial DNA depletion. This pathogenetic mechanism should be considered in infants with multiple respiratory chain defects and variable tissue expression.
Acidosis, Lactic↗