Carlo Dionisi-Vici

Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation.

Human mitochondrial trifunctional protein (TFP) is a heterooctamer of four alpha- and four beta-subunits that catalyzes three steps in the beta-oxidation spiral of long-chain fatty acids. TFP deficiency causes a Reye-like syndrome, cardiomyopathy, or sudden, unexpected death. We delineated the molecular basis for TFP deficiency in two patients with a unique phenotype characterized by chronic progressive polyneuropathy and myopathy without hepatic or cardiac involvement. Single-stranded conformation variance and nucleotide sequencing identified all patient mutations in exon 9 of the alpha-subunit. One patient is homozygous for the T845A mutation that substitutes aspartic acid for valine at residue 246. The second patient is a compound heterozygote for the T914A that substitutes asparagine for isoleucine at residue 269 and a C871T that creates a premature termination at residue 255. Allele-specific oligonucleotide hybridization studies revealed undetectable levels of the mRNA corresponding to the mutant allele carrying the termination codon. This study suggests a novel genotype-phenotype correlation in TFP deficiency; that is, mutations in exon 9 of the alpha-subunit, which encodes a linker domain between the NH2-terminal hydratase and the COOH-terminal 3-hydroxyacyl-CoA dehydrogenase, result in a unique neuromuscular phenotype.

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.

N-acetylaspartylglutamate in Canavan disease: an adverse effector?

Abstract We measured N-acetylaspartate and its precursor/product N-acetylaspartylglutamate (NAAG) in urine of patients with Canavan disease using capillary zone electrophoresis. Abnormal levels of NAAG were found in 32 of 43 patients examined. Elevated NAAG was also present in the CSF of one patient. Given that NAAG may interfere with N-methyl-D-aspartate receptor function, the occurrence of high levels of NAAG in patients urine conceivably represents a participating factor in the pathogenesis of Canavan disease.nConclusion The biochemical role of N-acetylaspartylglutamate and its relationship to glutamatergic function may be relevant to the pathogenesis of Canavan disease.

Intravenous immune globulin in lysinuric protein intolerance

In addition to systemic manifestations with skeletal, pulmonary, renal, and haematological signs, lysinuric protein intolerance (LPI), a membrane transport defect of cationic amino acids, is often complicated by severe life-threatening immunological manifestations. A 10-year-old boy with LPI who exhibited a severe systemic immunohaematological disease is described here. This patient showed cutaneous lesions similar to the subacute form of systemic lupus erythematosus, severe anaemia and dysproteinaemia, and a marked reduction of circulating T lymphocytes, mainly the CD4+ cells. In vitro bone marrow cell culture studies showed that addition of patients serum induced macrophage proliferation and inhibited erythroid progenitor cell growth. Treatment with high-dose intravenous immune globulin resolved most of the clinical and laboratory abnormalities.

Skin and Hair Disorders

A correct classification of skin and hair signs as well as the knowledge of characteristic cutaneous symptoms is important to understand and diagnose inherited metabolic diseases. n n nThe profile of cutaneous signs, the age of the patient when manifestations initially occurred and the presence of associated symptoms, is of particular importance. n n nDermatological evaluation can help identify complications of the disease or side effects of treatments. n n nCutaneous signs of several types often occur in a single given disorder. n n nThe principal lesions can be grouped into the following main groups: vascular lesions, skin eruptions, ichthyosis, papular and nodular skin lesions, abnormal pigmentation, photosensitivity, hair disorders, and skin laxity.

Emergency Diagnostic Procedures and Emergency Treatment

Metabolic emergencies need to be recognized early, and the initiation of appropriate treatment without any delay determines the overall outcome. A significant proportion of patients with inborn errors of metabolism are at risk of developing a metabolic emergency at some time of their life, particularly those children affected by an inborn error of metabolism that manifests as an acute intoxication. These patients usually present as a neonate – typically after an initial symptom-free interval of some days – in an emergency situation. Treatment needs to be initiated immediately even without having arrived at the exact diagnosis.

Metabolic and Mitochondrial Ataxias

Publisher Summary Metabolic determinants of ataxia have conspicuously expanded in the last decade, particularly in the field of mitochondrial encephalopathies. Moreover, there are numerous advances in understanding the pathogenetic mechanisms of other metabolic conditions that are already known before, especially for lysosomal disorders, for Niemann-Pick type C, for some organic acidurias, and for congenital disorders of glycosilation. This chapter explains mitochondrial encephalopathies because they are a frequent and rapidly expanding cause of metabolic derangement causing ataxia. The term mitochondrial disorders is applied to the clinical syndromes associated with abnormalities of the common final pathway of the mitochondrial energy metabolism. From a genetic standpoint, the respiratory chain is unique, since it is formed through the complementation of two distinct genetic systems, the nuclear and the mitochondrial genomes. Nuclear genes provide most of the subunits of the respiratory complexes, the factors that control their intra mitochondrial transport, assembly, and turnover, as well as the enzymes for the synthesis of prosthetic groups.

The Skin as a Clue for the Diagnosis of Inherited Metabolic Disorders

Dermatology may be considered as the science of skin biology, skin disease, and treatment, but it is particularly a special art of visual perception to detect clues for phenotype categorization.