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Carlo Dionisi-Vici

Publications and source records attributed to Carlo Dionisi-Vici.

17 recordsLinked to original sources
PubMed2025

Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency: From metabolism to clinical implications.

PURPOSE: Ketone bodies represent an important energy source and can contribute much to the energy supply of the brain. Mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A synthase deficiency (HMGCS2D) is an autosomal recessive disorder of ketogenesis caused by biallelic variants in HMGCS2. Only 59 patients with this disorder have been reported so far. METHODS: We performed a comprehensive literature search to identify all published cases of HMGCS2D (n = 59). Additionally, the data of 16 patients with this disorder who are yet undescribed were collected. Clinical course, biochemical findings, and mutation data are highlighted and discussed. An overview on all HMGCS2 variants reported in patients is provided. RESULTS: Sixty-eight patients (91%) presented with an acute metabolic decompensation, mostly within the first year of life but beyond the neonatal period. Asymptomatic individuals were identified in several families. Six patients (8%) had died, mainly during the initial metabolic crisis. The neurologic long-term outcome of surviving patients was favorable with almost all patients (98%) showing normal development. Only 1 variant was identified to be common, (HMGCS2) NM_005518.4:c.634G>A p.(Gly212Arg), and found in 6 families. No genotype-phenotype correlation can be established. CONCLUSION: This comprehensive data analysis provides an overview on all published patients reported with HMGCS2D, including a list of HMGCS2 variants identified in affected individuals.

Child↗
PubMed2006

Novel CLN1 mutation in two Italian sibs with late infantile neuronal ceroid lipofuscinosis.

We detected a novel CLN1 mutation (c.125-15t>g) in two Italian siblings. The clinical phenotype is that of a variant late-infantile neuronal ceroid lipofuscinosis and consisted of early-onset visual loss, psychomotor deterioration, and seizures. Ultrastructurally, granular osmiophilic deposits were found in skin biopsy of both patients. The novel mutation occurs in the acceptor sequences for splicing and leads to skipping of multiple exons. This predicts a protein lacking part or all of the active site of the enzyme and the palmitate-binding pocket. Consequently, biochemical activity of the palmitoyl protein thioesterase-1 enzyme was drastically reduced. The new mutation was not identified in a large set of ethnically matched control chromosomes. Our findings support the notion that CLN1 patients are not rare in Southern Europe and facilitate DNA-based mutation and carrier testing in this family.

Adolescent↗
PubMed2006

Hypertrophic cardiomyopathy, cataract, developmental delay, lactic acidosis: a novel subtype of 3-methylglutaconic aciduria.

3-Methylglutaconic aciduria is the biochemical marker of several inherited metabolic diseases. Four types of 3-methylglutaconic aciduria can be distinguished. In the type I form, accumulation of 3-methylglutaconate is due to deficient activity of 3-methylglutaconyl-CoA hydratase, an enzyme of the leucine degradation pathway. In the other forms, 3-methylglutaconic acid is not derived from leucine but is of unidentified origin, possibly derived from other metabolic pathways, such as mevalonate metabolism. We report five patients, all presenting a severe early-onset phenotype characterized by 3-methylglutaconic aciduria, hypertrophic cardiomyopathy, cataract, hypotonia/developmental delay, lactic acidosis, and normal 3-methylglutaconyl-CoA hydratase activity. This peculiar phenotype, for which a primary mitochondrial disorder is hypothesized, identifies a novel subtype of 3-methylglutaconic aciduria.

Acidosis, Lactic↗
PubMed2006

Methylmalonic and propionic aciduria.

Methylmalonic and propionic aciduria (PA) are the most frequent forms of branched-chain organic acidurias. These autosomal recessive disorders result from deficient activity of methylmalonyl-CoA mutase and propionyl-CoA carboxylase, respectively. Clinically, acute or chronic neurologic signs are caused by the accumulation of toxic compounds proximal to the metabolic block. Phenotype varies from severe neonatal-onset forms with high mortality and poor outcome to milder forms with a later onset. In both cases the clinical course is dominated by the risk of relapses of life-threatening episodes of metabolic decompensation and of severe organ failure. Despite improvement of treatment, the overall outcome remains disappointing with no major differences between the two diseases. The diagnosis is based on the presence of characteristic compounds in body fluids as detected by organic acid analysis in urine and acylcarnitine profile in blood. Therapy is based on low-protein high-energy diet, carnitine supplementation, and metronidazole. Some patients with methylmalonic aciduria (MMA) respond to pharmacological doses of vitamin B12. Given the poor long-term prognosis, liver transplantation has been recently attempted as an alternative therapy to conventional medical treatment to cure the underlying metabolic defect. Nevertheless, the overall experience to date does not clearly demonstrate its effectiveness in preventing further deterioration or improving survival and quality of life. The recent implementation of neonatal screening by electrospray tandem mass spectrometry has decreased early mortality and improved the short-term outcome, without changing the detection rate of both diseases in the screening population compared to clinically detected cases. However, the limited number of patients and the short duration of their follow-up do not yet permit drawing final conclusions on its effect on the long-term outcome of methylmalonic and propionic acidemia.

Humans↗
PubMed2004

Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein.

Ethylmalonic encephalopathy (EE) is a devastating infantile metabolic disorder affecting the brain, gastrointestinal tract, and peripheral vessels. High levels of ethylmalonic acid are detected in the body fluids, and cytochrome c oxidase activity is decreased in skeletal muscle. By use of a combination of homozygosity mapping, integration of physical and functional genomic data sets, and mutational screening, we identified GenBank D83198 as the gene responsible for EE. We also demonstrated that the D83198 protein product is targeted to mitochondria and internalized into the matrix after energy-dependent cleavage of a short leader peptide. The gene had previously been known as "HSCO" (for hepatoma subtracted clone one). However, given its role in EE, the name of the gene has been changed to "ETHE1." The severe consequences of its malfunctioning indicate an important role of the ETHE1 gene product in mitochondrial homeostasis and energy metabolism.

Amino Acid Sequence↗
PubMed2004

Molecular and functional analysis of SLC25A20 mutations causing carnitine-acylcarnitine translocase deficiency.

The enzyme carnitine-acylcarnitine translocase (CACT) is involved in the transport of long-chain fatty acids into mitochondria. CACT deficiency is a life-threatening, recessively inherited disorder of lipid beta-oxidation which manifests in early infancy with hypoketotic hypoglycemia, cardiomyopathy, liver failure, and muscle weakness. We report here the clinical, biochemical, and molecular features of six CACT-deficient patients from Italy, Spain, and North America who exhibited significant clinical heterogeneity. In five patients (Patients 1, 2, 4, 5, and 6) the disease manifested in the neonatal period, while the remaining patient (Patient 3), the younger sibling of an infant who had died with clinical suspicion of fatty acid oxidation defect, has been treated since birth and was clinically asymptomatic at 4.5 years of age. Patients 1 and 4 were deceased within 6 months from the onset of this study, while the remaining four are still alive at 8, 4.5, 3.5, and 2 years, respectively. Sequence analysis of the CACT gene (SLC25A20) disclosed five novel mutations and three previously reported mutations. Three patients were homozygous for the identified mutations. Two of the novel mutations (c.718+1G>C and c.843+4_843+50del) altered the donor splice site of introns 7 and 8, respectively. The 47-nt deletion in intron 8 caused both skipping of exon 8 only and skipping of exons 6-8. Four mutations [[c.159dupT;c.163delA] ([p.Gly54Trp;p.Thr55Ala]) c.397C>T (p.Arg133Trp), c.691G>C (p.Asp231His), and c.842C>T (p.Ala281Val)] resulted in amino acid substitutions affecting evolutionarily conserved regions of the protein. Interestingly, one of these exonic mutations (p.Ala281Val) was associated with a splicing defect also characterized by skipping of exons 6-8. The deleterious effect of the p.Arg133Trp substitution was demonstrated by measuring CACT activity upon expression of the normal and the mutant protein in E. coli and functional reconstitution into liposomes. Combined analysis of clinical, biochemical, and molecular data failed to indicate a correlation between the phenotype and the genotype.

Amino Acid Sequence↗
PubMed2003

The mitochondrial ornithine transporter. Bacterial expression, reconstitution, functional characterization, and tissue distribution of two human isoforms.

Two isoforms of the human ornithine carrier, ORC1 and ORC2, have been identified by overexpression of the proteins in bacteria and by study of the transport properties of the purified proteins reconstituted into liposomes. Both transport L-isomers of ornithine, lysine, arginine, and citrulline by exchange and by unidirectional mechanisms, and they are inactivated by the same inhibitors. ORC2 has a broader specificity than ORC1, and L- and D-histidine, L-homoarginine, and D-isomers of ornithine, lysine, and ornithine are all substrates. Both proteins are expressed in a wide range of human tissues, but ORC1 is the predominant form. The highest levels of expression of both isoforms are in the liver. Five mutant forms of ORC1 associated with the human disease hyperornithinemia-hyperammonemia-homocitrullinuria were also made. The mutations abolish the transport properties of the protein. In patients with hyperornithinemia-hyperammonemia-homocitrullinuria, isoform ORC2 is unmodified, and its presence compensates partially for defective ORC1.

Amino Acid Transport Systems, Basic↗
PubMed2003

Characteristic acylcarnitine profiles in inherited defects of peroxisome biogenesis: a novel tool for screening diagnosis using tandem mass spectrometry.

Patients with inherited defects of peroxisomal metabolism, a class of diseases with marked clinical and genetic heterogeneity, show a characteristic phenotype in most cases with severe neurologic impairment, craniofacial abnormalities, and hepatic and kidney dysfunction. For the differential diagnosis of clinically suspected cases, a complex biochemical and genetic approach is required. Analysis of plasma very-long-chain fatty acids is a reliable screening method to detect most but not all peroxisomal disorders. To study the potential presence of abnormal acylcarnitine species in plasma and blood, we screened by tandem mass spectrometry a series of patients affected by a peroxisome biogenesis disorder (PBD) and compared the results with those obtained in patients with isolated peroxisomal defects (e.g. D-bifunctional protein deficiency, X-linked adrenoleukodystrophy) and mitochondrial long-chain fatty acid oxidation defects. The most relevant finding observed in plasma of patients with PBD was a significant increase of long-chain dicarboxylic C16- and C18-carnitine, i.e. hexadecanedioyl- and octadecanedioyl-carnitine, with high dicarboxylycarnitine/monocarboxylylcarnitine ratio. Elevation of very long-chain acylcarnitines C24- and C26-, i.e. lignoceroyl- and cerotoyl-carnitine, was detected in some PBDs and in D-bifunctional protein deficiency. Similar abnormalities were also found in neonatal screening blood spots. Detection of these compounds alone, in the absence of other shorter-chain acylcarnitines, is highly specific and characteristic of PBD, as confirmed by the differing profiles observed in patients with adrenoleukodystrophy and mitochondrial long-chain fatty acid oxidation defects. Our study adds a novel method to the diagnosis of PBD, which may also be of benefit for future neonatal mass screening programs based on acylcarnitine profiling.

Carnitine↗
PubMed2003

Tyrosine hydroxylase deficiency causes progressive encephalopathy and dopa-nonresponsive dystonia.

Tyrosine hydroxylase (TH) is the key enzyme in the biosynthesis of the catecholamines dopamine, epinephrine, and norepinephrine. Recessively inherited deficiency of TH was recently identified and incorporated into recent concepts of genetic dystonias as the cause of recessive Dopa-responsive dystonia or Segawa's syndrome in analogy to dominantly inherited GTP cyclohydrolase I deficiency. We report four patients with TH deficiency and two with GTP cyclohydrolase I deficiency. Patients with TH deficiency suffer from progressive infantile encephalopathy dominated by motor retardation similar to a primary neuromuscular disorder, fluctuating extrapyramidal, and ocular and vegetative symptoms. Intellectual functions are mostly compromised. Prenatally disturbed brain development and postnatal growth failure were observed. Treatment with levodopa ameliorates but usually does not normalize symptoms. Compared with patients with dominantly inherited GTP cyclohydrolase I deficiency, catecholaminergic neurotransmission is severely and constantly impaired in TH deficiency. In most patients, this results not in predominating dystonia, a largely nondegenerative condition, but in a progressive often lethal neurometabolic disorder, which can be improved but not cured by L-dopa. Investigations of neurotransmitter defects by specific cerebrospinal fluid determinations should be included in the diagnostic evaluation of children with progressive infantile encephalopathy.

Amino Acid Metabolism, Inborn Errors↗
PubMed2003

Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis.

Autosomal-recessive osteopetrosis is a severe genetic disease caused by osteoclast failure. Approximately 50% of the patients harbor mutations of the ATP6i gene, encoding for the osteoclast-specific a3 subunit of V-ATPase. We found inactivating ATP6i mutations in four patients, and three of these were novel. Patients shared macrocephaly, growth retardation and optic nerve alteration, osteosclerotic and endobone patterns, and high alkaline phosphatase and parathyroid hormone levels. Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae. Scarce hematopoietic cells and abundant fibrous tissue containing TRAP-positive putative osteoclast precursors were noted. In vitro osteoclasts were a3-negative, morphologically normal, with prominent clear zones and actin rings, and TRAP activity more elevated than in control patients. Podosomes, alphaVbeta3 receptor, c-Src, and PYK2 were unremarkable. Consistent with the finding in the bone biopsies, these cells excavated pits faintly stained with toluidine blue, indicating inefficient bone resorption. Bone marrow transplantation was successful in all patients, and posttransplant osteoclasts showed rescue of a3 subunit immunoreactivity.

Acid Phosphatase↗
PubMed2003

Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement.

OBJECTIVE: To determine the spectrum of presentation, including both clinical and biochemical abnormalities, and the clinical course in a cohort of patients with complete mitochondrial trifunctional protein (MTP) deficiency, a rare inborn error of mitochondrial fatty acid oxidation. STUDY DESIGN: A questionnaire was sent to the referring physicians from 25 unselected MTP-deficient patients. RESULTS: Twenty-one patients could be included. Questionnaires about four patients were not returned. Nine (43%) patients presented with rapidly progressive clinical deterioration; six (67%) of them had hypoketotic hypoglycemia. The remaining 12 patients presented with a much more insidious disease with nonspecific chronic symptoms, including hypotonia (100%), cardiomyopathy (73%), failure to thrive, or peripheral neuropathy. Ten patients (48%) presented in the neonatal period. Mortality was high (76%), mostly attributable to cardiac involvement. Two patients who were diagnosed prenatally died despite treatment. CONCLUSION: Complete MTP deficiency often presents with nonspecific symptomatology, which makes clinical recognition difficult. Hypotonia and cardiomyopathy are common presenting features, and the differential diagnosis of an infant with these signs should include MTP deficiency. In spite of early diagnosis and treatment, only a few patients with this condition have survived.

Cardiomyopathies↗
PubMed2002

Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy.

Primary systemic carnitine deficiency or carnitine uptake defect (OMIM 212140) is a potentially lethal, autosomal recessive disorder characterized by progressive infantile-onset cardiomyopathy, weakness, and recurrent hypoglycemic hypoketotic encephalopathy, which is highly responsive to L-carnitine therapy. Molecular analysis of the SLC22A5 (OCTN2) gene, encoding the high-affinity carnitine transporter, was done in 11 affected individuals by direct nucleotide sequencing of polymerase chain reaction products from all 10 exons. Carnitine uptake (at Km of 5 microM) in cultured skin fibroblasts ranged from 1% to 20% of normal controls. Eleven mutations (delF23, N32S, and one 11-bp duplication in exon 1; R169W in exon 3; a donor splice mutation [IVS3+1 G > A] in intron 3; frameshift mutations in exons 5 and 6; Y401X in exon 7; T440M, T468R and S470F in exon 8) are described. There was no correlation between residual uptake and severity of clinical presentation, suggesting that the wide phenotypic variability is likely related to exogenous stressors exacerbating carnitine deficiency. Most importantly, strict compliance with carnitine from birth appears to prevent the phenotype.

Cardiomyopathies↗
PubMed2002

Ethylmalonic encephalopathy: further clinical and neuroradiological characterization.

Ethylmalonic encephalopathy (EE) is a rare metabolic disorder with an autosomal recessive mode of inheritance that is clinically characterized by neuromotor delay, hyperlactic acidemia, recurrent petechiae, orthostatic acrocyanosis, and chronic diarrhea. Increased urinary levels of ethylmalonic acid and methylsuccinic acid are the main biochemical features of the disorder. We report on two patients affected by EE who showed different clinical and neuroradiological patterns. Patient 1 presented with a chronic clinical course characterized by very slow neuromotor deterioration, ataxia, and dysarthria. In contrast, patient 2 had an acute neonatal onset with severe neuromotor retardation, severe generalized hypotonia, and intractable seizures. Neuroradiological follow-up of patient 1 detected a diffuse hyperintensity on the T2 images at the basal ganglia which remained stable during a period of four years. Patient 2, in contrast, showed a rapid process of cerebral, and in part, cerebellar atrophy. On the basis of our observations, we reviewed the data published in the literature and tried to delineate the natural history of EE, which appears to be characterized by a wide spectrum of severity in the clinical course. No reports on neuroradiological follow-up of EE patients are available in the literature with which to compare our data. Finally, both patients showed a muscle COX deficiency. The pathogenetic implications of such a biochemical finding will be also discussed.

Brain Diseases, Metabolic, Inborn↗
PubMed2002

The ketogenic diet in children, adolescents and young adults with refractory epilepsy: an Italian multicentric experience.

PURPOSE: This collaborative study by three Italian groups of child neuropsychiatrists was carried on to evaluate the efficacy and safety of the classic 4:1 ketogenic diet as add-on treatment in refractory partial or generalized epilepsy in children, adolescents and young adults. METHODS: We performed a prospective add-on study in 56 refractory epilepsy young patients (age 1-23 years, mean 10.4 years), all with both symptomatic and cryptogenic, generalized or partial epilepsies. Child neuropsychiatrists worked with nutritional team for sample selection and patients management. The ketogenic diet was added to the baseline antiepileptic drugs and the efficacy was rated according to seizure type and frequency. During treatment, seizure frequency, side effects, urine and blood ketone levels and other parameters were systematically evaluated. RESULTS: Patients have been treated for 1-18 months (mean 5 months). A >50% reduction in seizure frequency was gained in 37.5 and 26.8% of patients after 3 and 6 months, respectively, at 12 months, this number fell by 8.9%. No significant relationship between diet efficacy and seizure or epilepsy type, age at diet onset, sex and etiology of epilepsy was noted. Nevertheless, it seems noteworthy that 64% of our patients with neuronal migration disorders improved on this diet. Adverse effects occurred, mainly in the first weeks of treatment, in 32 patients (57.1%), but were generally mild and transient. In seven patients (12.5%) it was possible to withdraw one to two AED after 3-4 months on ketogenic diet. CONCLUSION: This initial experience with the ketogenic diet was effective in difficult-to-treat patients with partial and generalized epilepsies, though its efficacy dropped significantly by 9-12 months.

Adolescent↗
PubMed2002

Inborn errors of metabolism in the Italian pediatric population: a national retrospective survey.

OBJECTIVE: To estimate at the national level the overall and disease-specific incidence of inborn errors of metabolism not mass screened at birth. STUDY DESIGN: Prospective nonconcurrent study (1985-1997) on patients 0 to 17 years of age, diagnosed in 23 Italian pediatric reference centers. RESULTS: Cases (n = 1935) were recruited representing an incidence of 1:3707 live births for approximately 200 diseases. In the last 5 years the incidence was 1:2758, reflecting improved diagnostic facilities, better coverage, increased medical awareness, and newly discovered diseases. In this period, the most frequent classes of diseases were lysosomal storage disease, 1:8275; disorders of carbohydrate metabolism, 1:19,532; organic acidopathies, 1:21,422; and primary lactic acidemias, 1:27,106. The most frequent individual diseases were Gaucher type I, 1:40,247; glycogenosis type 1a, 1:57,746; methylmalonic acidurias, 1:61,775; and ornithine transcarbamylase deficiency, 1:69,904. The incidence of diseases potentially identifiable with the use of a new neonatal mass screening technique is 1:6200. Of surviving patients, 11% reached adulthood by the end of the study. CONCLUSIONS: Inborn errors of metabolism constitute a highly heterogeneous category of rare diseases, representing a relevant cause of morbidity and mortality in childhood. This study quantifies the minimum size of the disease burden, providing useful tools for public health and health policy planning.

Adolescent↗
PubMedDate not supplied

'Classical' organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry.

'Classical organic acidurias' comprise isovaleric aciduria, propionic aciduria and methylmalonic aciduria. Available data from the literature suggest that the use of 'new' therapeutic strategies has improved survival but has not modified neurodevelopment. Progressive neurocognitive deterioration is almost invariably present in propionic and methylmalonic acidurias, while large-scale studies on the long-term outcome of patients with isovaleric aciduria are still lacking. In order to answer to some of the questions suggested by Wilson and Jungner in 1968 about the criteria of disease screening, we compared the natural history of patients with 'classical' organic acidurias diagnosed on clinical bases to those diagnosed through neonatal mass screening using tandem mass spectrometry. Decreased early mortality, less severe symptoms at diagnosis, and more favourable short-term neurodevelopmental outcome were recorded in patients identified through expanded newborn screening. The short duration of follow-up so far does not allow us to draw final conclusions about the effects of newborn screening on long-term outcome. The evaluation of the effect of neonatal screening on the detection rate of these three diseases showed that the incidence of isovaleric aciduria was significantly higher in the screening population than in clinically detected cases, with no changes for propionic and methylmalonic acidurias. Further multicentre longitudinal studies are needed to assess the usefulness of expanded newborn screening for 'classical' organic acidurias and to better understand the clinical spectrum of these diseases. This paper describes the long-term outcome and the impact of expanded newborn screening on the so-called 'classical' organic acidurias (propionic aciduria, methylmalonic aciduria and isovaleric aciduria).

Amino Acid Metabolism, Inborn Errors↗