Ades LC, Gedeon AK, Wilson MJ, Latham M, Partington MW, Mulley JC, Nelson J, Lui K, Sillence DO.
Barth syndrome: clinical features and confirmation of gene localisation to distal Xq28.
Am J Med Genet 1993;45:327-334.
Barth syndrome is an X-linked disorder characterised by cardioskeletal myopathy of variable severity usually fatal in childhood, and neutropenia. We ascertained a large pedigree with affected males in 3 generations. All affected males had dilated cardiomyopathy, with endocardial fibroelastosis (EFE) in some. The locus for Barth syndrome in this family was found to be closely linked to DXS52 (z = 2.78, theta = 0.0). The family was nonrecombinant for DXS52 in distal Xq28, but recombinant for DXS374 which maps proximal to DXS52. This localised Barth syndrome distal to DXS374, confirming a previous localisation to distal Xq28. As yet there is no evidence for genetic heterogeneity of Barth syndrome.


Adwani SS, Whitehead BF, Rees PG, Whitmore P, Fabre JW, Elliott MJ, de Leval MR.
Heart transplantation for dilated cardiomyopathy.
Arch Dis Child 1995;73:447-452.
Between 1988 and 1994, 23 patients underwent heart transplantation for dilated cardiomyopathy. The age of the 13 boys and 10 girls was from 8 months to 16 years (mean 7.1 years). Selection criteria included failure to thrive despite maximal antifailure treatment and/or intravenous inotrope dependence. The aetiology of cardiomyopathy was idiopathic (n = 13), congenital (n = 3), anthracycline induced (n = 4), Barth's syndrome (n = 1), and maternal systemic lupus erythematosus (n = 2). The waiting period of heart transplantation ranged from one day to 147 days (mean 22 days). Maintenance immunosuppression included cyclosporin, azathioprine, and prednisolone. Follow up after transplantation was from one month to 62 months (median 27 months) with a mean actuarial survival of 95% at one year and 87% at three years. Four patients developed coronary artery disease, one of whom died as a consequence 15 months after heart transplantation. Heart transplantation has emerged as an acceptable therapeutic option, at least in the short term, for patients with dilated cardiomyopathy.


Adwani SS, Whitehead BF, Rees PG, Morris A, Turnball DM, Elliott MJ, de Leval MR.
Heart transplantation for Barth syndrome.
Pediatr Cardiol 1997;18:143-145.
Barth syndrome is an X-linked recessive disorder comprising dilated cardiomyopathy, muscular hypotonia, and cyclical neutropenia. Affected children usually die during infancy as a consequence of septicemia, cardiac failure, or both. We report a patient with Barth syndrome who underwent successful heart transplantation.


al Aqeel A, Rashed M, Ozand PT, Brismar J, Gascon GG, al Odaib A, Dabbagh O.
3-Methylglutaconic aciduria: ten new cases with a possible new phenotype.
Brain Dev 1994;16:23-32.
3-Methylglutaconic aciduria is an organic aciduria with diverse phenotypic presentations. In more than half of the cases it is a 'neurologic or silent organic aciduria', and, except for one subtype, the biochemical defect is unknown. This report describes 10 new patients. Four of them presented with early global neurologic involvement and arrested development. They rapidly became demented, developed myoclonus or tonic-clonic seizures, spastic quadriplegia, deafness and blindness, and died. Three had acidosis and hypoglycemia neonatally; later, myoclonus and deafness, and eventually severe mental retardation and spastic quadriplegia developed. One patient died. In three children who presented with sudden onset of extrapyramidal tract symptoms, with or without optic atrophy, the clinical presentation was significantly different from that described either for 'unspecified' type or for Costeff syndrome. All three patients showed clinical improvement soon after treatment with coenzyme Q.


Bakkeren JA, Sengers RC, Ruitenbeek W, Trijbels JM.
3-Methylglutaconic aciduria in a patient with a disturbed mitochondrial energy metabolism [letter].
Eur J Pediatr 1992;151:313.



Barth PG, Scholte HR, Berden JA, Van dK-VMJM, Luyt-Houwen IE, Van tV-KET, Van dHJJ, Sobotka-Plojhar MA.
An X-linked mitochondrial disease affecting cardiac muscle, skeletal muscle and neutrophil leucocytes.
Journal of the Neurological Sciences 1983;62:327-355.



Barth PG, Van den Bogert C, Bolhuis PA, Scholte HR, van Gennip AH, Schutgens RB, Ketel AG.
X-linked cardioskeletal myopathy and neutropenia (Barth syndrome): respiratory-chain abnormalities in cultured fibroblasts.
J Inherit Metab Dis 1996;19:157-160.



Besley GT, Lendon M, Broadhead DM, Till J, Heptinstall LE, Phillips B.
Mitochondrial complex deficiencies in a male with cardiomyopathy and 3-methylglutaconic aciduria.
J Inherit Metab Dis 1995;18:221-223.



Bies RD.
X-linked dilated cardiomyopathy [letter; comment].
N Engl J Med 1994;330:368-369.



Bione S, D'Adamo P, Maestrini E, Gedeon AK, Bolhuis PA, Toniolo D.
A novel X-linked gene, G4.5. is responsible for Barth syndrome.
Nat Genet 1996;12:385-389.
Barth syndrome is a severe inherited disorder, often fatal in childhood, characterized by cardiac and skeletal myopathy, short stature and neutropenia. The disease has been mapped to a very gene-rich region in distal portion of Xq28. We now report the identification of unique mutations in one of the genes in this region, termed G4.5, expressed at high level in cardiac and skeletal muscle. Different mRNAs can be produced by alternative splicing of the primary G4.5 transcript, encoding novel proteins that differ at the N terminus and in the central region. The mutations introduce stop codons in the open reading frame interrupting translation of most of the putative proteins (which we term 'tafazzins'). Our results suggest that G4.5 is the genetic locus responsible for the Barth syndrome.


Bleyl SB, Mumford BR, Thompson V, Carey JC, Pysher TJ, Chin TK, Ward K.
Neonatal, lethal noncompaction of the left ventricular myocardium is allelic with Barth syndrome.
Am J Hum Genet 1997;61:868-872.
Loss-of-function mutations in the G4.5 gene have been shown to cause Barth syndrome (BTHS), an X-linked disorder characterized by cardiac and skeletal myopathy, short stature, and neutropenia. We recently reported a family with a severe X-linked cardiomyopathy described as isolated noncompaction of the left ventricular myocardium (INVM). Other findings associated with BTHS (skeletal myopathy, neutropenia, growth retardation, elevated urinary organic acids, and mitochondrial abnormalities) were either absent or inconsistent. A linkage study of the X chromosome localized INVM to the Xq28 region near the BTHS locus, suggesting that these disorders are allelic. We screened the G4.5 gene for mutations in this family with SSCP and direct sequencing and found a novel glycine-to-arginine substitution at position 197. This position is conserved in a homologous Caenorhabditis elegans protein. We conclude that INVM is a severe allelic variant of BTHS with a specific effect on the heart. This finding provides further structure-function information about the G4.5 gene product and has implications for unexplained cases of severe infantile hypertrophic cardiomyopathy in males.


Bleyl SB, Mumford BR, Brown-Harrison MC, Pagotto LT, Carey JC, Pysher TJ, Ward K, Chin TK.
Xq28-linked noncompaction of the left ventricular myocardium: prenatal diagnosis and pathologic analysis of affected individuals.
Am J Med Genet 1997;72:257-265.
Isolated noncompaction of the left ventricular myocardium (INVM) is characterized by the presence of numerous prominent trabeculations and deep intertrabecular recesses within the left ventricle, sometimes also affecting the right ventricle and interventricular septum. Familial occurrence of this disorder was described previously. We present a family in which 6 affected individuals demonstrated X-linked recessive inheritance of this trait. Affected relatives presented postnatally with left ventricular failure and arrhythmias, associated with the pathognomonic echocardiographic findings of INVM. The usual findings of Barth syndrome (neutropenia, growth retardation, elevated urinary organic acids, low carnitine levels, and mitochondrial abnormalities) were either absent or found inconsistently. Fetal echocardiograms obtained between 24-30 weeks of gestation in 3 of the affected males showed a dilated left ventricle in one heart, but were not otherwise diagnostic of INVM in any of the cases. Four of the affected individuals died during infancy, one is in cardiac failure at age 8 months, and one is alive following cardiac transplant at age 9 months. The hearts from infants who died or underwent transplantation appeared, on gross examination, to be enlarged, with coarse, deep ventricular trabeculations and prominent endocardial fibroelastosis. Histologically, there were loosely organized fascicles of myocytes in subepicardial and midmyocardial zones of both ventricles, and the myocytes showed thin, often angulated fibers with prominent central clearing and reduced numbers of filaments. Markedly elongated mitochondria were present in some ventricular myocytes from one specimen, but this finding was not reproducible. Genetic linkage analysis has localized INVM to the Xq28 region, where other myopathies with cardiac involvement have been located.


Bolhuis PA, Hensels GW, Hulsebos TJ, Baas F, Barth PG.
Mapping of the locus for X-linked cardioskeletal myopathy with neutropenia and abnormal mitochondria (Barth syndrome) to Xq28.
American Journal of Human Genetics 1991;48:481-485.



Broide E, Elpeleg O, Lahat E.
Type IV 3-methylglutaconic (3-MGC) aciduria: a new case presenting with hepatic dysfunction.
Pediatr Neurol 1997;17:353-355.
We describe a new patient with type IV 3-methylglutaconic aciduria who presented with a clinical picture simulating a primary hepatic disorder subsequently followed with progressive neurologic impairment and an magnetic resonance imaging picture of Leigh syndrome.


Cardonick EH, Kuhlman K, Ganz E, Pagotto LT.
Prenatal clinical expression of 3-methylglutaconic aciduria: Barth syndrome.
Prenat Diagn 1997;17:983-988.



Chitayat D, Chemke J, Gibson KM, Mamer OA, Kronick JB, McGill JJ, Rosenblatt B, Sweetman L, Scriver CR.
3-Methylglutaconic aciduria: a marker for as yet unspecified disorders and the relevance of prenatal diagnosis in a 'new' type ('type 4').
J Inherit Metab Dis 1992;15:204-212.
The Mendelian disorder known as 3-methylgutaconic aciduria (McKusick 250950) gives evidence of allelic and locus heterogeneity. Type 1 has a mild clinical phenotype and confirmed 3-methylgutaconyl-CoA hydratase deficiency; inheritance is autosomal recessive. Other forms have major clinical manifestations and subdivide into X-linked (type 2), a form in Iraqi Jews with optic atrophy (so-called type 3); and untyped (putative autosomal recessive) forms without identified enzyme defects. In the latter, 3-methylglutaconic aciduria may simply be a marker for another metabolic disorder. We describe a male proband with 3-methylglutaconic aciduria designated here as 'type 4' (autosomal recessive, with severe psychomotor phenotype and cerebellar dysgenesis). He is the offspring of Italian consanguineous parents. Born with congenital malformations, he has been followed for 18 years, showing profound developmental delay and cerebellar dysgenesis. Measures of hydratase activity in cultured fibroblasts from the proband and 11 additional patients (two with type 1 disease, 9 with either type 2 or an unspecified form) revealed deficient enzyme activity in type 1 cases and normal activity in the proband and the other 11 cases. Two of the untyped cases probably have 3-methylglutaconic aciduria of the type described here. Prenatal diagnosis in the form described here may be feasible by analysis of amniotic fluid metabolites in pregnancies at risk if the mother does not entirely remove elevated concentrations. A female sibling of the proband had normal metabolite values in amniotic fluid. Postnatal follow-up confirmed absence of the disease. We give the normal values for amniotic fluid and results on these additional fetuses at risk (none affected).


Chow CS, Behlen LS, Uhlenbeck OC, Barton JK.
Recognition of tertiary structure in tRNAs by Rh(phen)2phi3+, a new reagent for RNA structure-function mapping.
Biochemistry 1992;31:972-982.
With photoactivation Rh(phen)2phi3+ promotes strand cleavage at sites of tertiary interaction in tRNA. The rhodium complex, which binds double-helical DNA by intercalation in the major groove, yields no cleavage in double-helical regions of the RNA or in unstructured single-stranded regions. Instead, Rh(phen)2phi3+ appears to target regions which are structured so that the major groove is open and accessible for stacking with the complex, as occurs where bases are triply bonded. So as to examine the specificity of this novel reagent and to evaluate its use in probing structural changes in RNAs, cleavage studies have been conducted on two structurally characterized tRNAs, tRNA(Phe) and tRNA(Asp) from yeast, the unmodified yeast tRNA(Phe) transcript, and a chemically modified tRNA(Phe), as well as on a series of tRNA(Phe) mutants. On tRNA(Phe) strong cleavage is observed at residues G22, G45, U47, psi 55, and U59; weaker cleavage is observed at A44, m7G46, and C48. On tRNA(Asp) cleavage is found at residues A21 through G26, psi 32, and U48, with minor cleavage apparent at A44, G45, A46, psi 55, U59, and U60. There is a striking similarity in cleavage observed on these tRNAs, and the sites of cleavage mark regions of tertiary folding. Cleavage on the unmodified tRNA(Phe) transcript resembles closely that found on native yeast tRNA(Phe), but additional sites, primarily in the anticodon loop and stem, are evident. The results indicate that globally the structures containing or lacking the modified bases appear to be the same; the differences in cleavage observed may reflect a loosening or alteration in the structure due to the absence of the modified bases. Cleavage results on mutants of tRNA(Phe) illustrate Rh(phen)2phi3+ as a sensitive probe in characterizing tRNA tertiary structure. Results are consistent with other assays for structural or functional changes. Uniquely, Rh(phen)2phi3+ appears to target directly sites of tertiary interaction. Cleavage results on mutants which involve base changes within the triply bounded region of the molecule indicate that it is the structure of the triply bonded array rather than the individual nucleotides which are being targeted. Chemical modification to promote selective depurination of the third base (m7G46) involved in the triple in the folded, native tRNA leads to the reduction of cleavage by the metal complex; this result shows directly the importance of the stacked triple base structure for recognition by the metal complex.(ABSTRACT TRUNCATED AT 400 WORDS)


Christodoulou J, McInnes RR, Jay V, Wilson G, Becker LE, Lehotay DC, Platt BA, Bridge PJ, Robinson BH, Clarke JT.
Barth syndrome: clinical observations and genetic linkage studies.
Am J Med Genet 1994;50:255-264.
Barth syndrome is an X-linked recessive condition characterized by skeletal myopathy, cardiomyopathy, proportionate short stature, and recurrent neutropenia, but with normal cognitive function. Some, but not all patients, exhibit carnitine deficiency and/or the presence of 3-methylglutaconic and ethylhydracylic acids in urine. Recently the mutation causing Barth syndrome was localised to the Xq28 region by linkage analysis. We report 6 cases of Barth syndrome from 4 families and highlight the fact that neuromuscular and cardiovascular symptoms and the severity of infections tend to improve with age, while short stature persists. Also previously unreported was myopathic facies and nasal quality to speech in our cases. The urinary organic acid abnormalities and plasma carnitine deficiency were inconsistent findings. We propose that they may be epiphenomena rather than indicators of the primary metabolic defect, and that the primary defect or defects in this disorder may lie in the mitochondrial electron transport chain.


Costeff H, Elpeleg O, Apter N, Divry P, Gadoth N.
3-Methylglutaconic aciduria in "optic atrophy plus".
Ann Neurol 1993;33:103-104.
Behr's syndrome consists of recessively inherited infantile optic atrophy, together with chronic neurological disturbances such as ataxia, extrapyramidal dysfunction, and juvenile spastic paresis. This syndrome was found to be relatively common among Iraqi Jews. For our study, 18 such patients underwent metabolic study. All 18 showed abnormally elevated excretion of 3-methylglutaconic acid in their urine. The basic enzymatic defect is as yet unknown. We recommend that patients with early optic atrophy, and especially those with motor dysfunction, be examined for this organic aciduria.


Costeff H, Elpeleg ON.
3-Methylglutaconic aciduria, type 3 [letter; comment].
Brain Dev 1995;17:226.



Costeff H, Apter N, Elpeleg ON, Prialnic M, Bohles HJ.
Ineffectiveness of oral coenzyme Q10 supplementation in 3- methylglutaconic aciduria, type 3.
Brain Dev 1998;20:33-35.
Coenzyme Q10 was administered under placebo controlled blinded crossover conditions to six subjects suffering from type 3 3- methylglutaconic aciduria ('optic atrophy plus'), following a report of benefit. Despite attainment of high plasma levels of coenzyme Q10, no clinical benefit was observed and there was no diminution of urinary excretion of 3-methylglutaconic acid.


Dasouki M, Buchanan D, Mercer N, Gibson KM, Thoene J.
3-Hydroxy-3-methylglutaric aciduria: response to carnitine therapy and fat and leucine restriction.
J Inherit Metab Dis 1987;10:142-146.
A female infant, born to first cousin parents, lapsed into coma with severe metabolic acidosis on day three of life. The gas chromatographic/mass spectrometric urinary organic acid profile showed marked elevation of the leucine metabolites 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxy-isovaleric acids. Less than 5% of the normal activity of the enzyme 3-hydroxy-3-methylglutaryl CoA lyase was detected in cultured skin fibroblasts. The patient's total and free carnitine was initially low but rose to normal levels after placing her on DL-carnitine (100 mg kg-1 d-1). On a diet providing 87 mg kg-1 d-1 of leucine and only 25% of total calories as fat and 2 g kg-1 d-1 protein, the concentration of the urinary organic acids fell markedly. She is now 15 months old with normal growth and development. This regimen appears effective in the early treatment of 3-hydroxy-3-methylglutaric aciduria.


de Koning TG, Duran M, Dorland L, Berger R, Poll-The BT.
Maternal 3-methylglutaconic aciduria associated with abnormalities in offspring [letter].
Lancet 1996;348:887-888.



Dodelson de Kremer R, Kelley RI, Depetris de Boldini C, Paschini de Capra A, Corbella L, Givogri I, Giner de Ayala A, Albarenque M.
[3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency as a cause of severe neurological damage]. [Spanish].
Medicina 1992;52:30-36.
This paper describes the first Argentine case of 3-hydroxy-3-methylglutaric aciduria, a genetic defect of ketogenesis and leucine catabolism step. At the age of 4 months, the patient presented a life-threatening episode of hypoglucemia, metabolic acidosis and hyperammonemia resembling Reye syndrome. The lack of urinary ketone bodies, normal levels of plasma aminoacids and normal urinary excretion of p-hydroxyphenolic acids, led us to look for a ketogenic defect. An abnormal profile of urinary organic acids detected by thin layer chromatography and later characterized and quantified by gas chromatography-mass spectrometry (Figs. 1, 2; Table 1), showed a marked increase in the acidic metabolites typical of the 3-hydroxy-3-methylglutaric aciduria: 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric and 3-hydroxyisovaleric acids. The activity of 3-hydroxy-3-methylglutaryl coenzyme A lyase was absent in white cell pellets and between 2-5% of the control values in skin fibroblasts (Table 2). Treatment of the disorder, mainly restricted leucine or low-protein diet and addition of L-carnitine had no significant effect on the severe neurological injuries present since the first illness. MRI of the brain, at the age of 1 year and 8 months, showed images in T1 suggestive of marked cerebral atrophy and in T2 hyperintensive images predominating in the right frontal and posterior parietal areas and of the punctiform lesions in the basal ganglia, particularly in the heads of both caudate nuclei.(ABSTRACT TRUNCATED AT 250 WORDS)


Draaisma JM, van Kesteren IC, Daniels O, Sengers RC.
Dilated cardiomyopathy with 3-methylglutaconic aciduria.
Pediatr Cardiol 1994;15:89-90.
The case of an infant with both dilated cardiomyopathy and 3-methylglutaconic aciduria is presented. The literature on this subject is reviewed.


Duran M, Ketting D, Wadman SK, Jakobs C, Schutgens RB, Veder HA.
Organic acid excretion in a patient with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency: facts and artefacts.
Clinica Chimica Acta 1978;90:187-193.



Duran M, Beemer FA, Tibosch AS, Bruinvis L, Ketting D, Wadman SK.
Inherited 3-methylglutaconic aciduria in two brothers--another defect of leucine metabolism.
Journal of Pediatrics 1982;101:551-554.



Duran M, Bruinvis L, Ketting D, Kamerling JP, Wadman SK, Schutgens RB.
The identification of (E)-2-methylglutaconic acid, a new isoleucine metabolite, in the urine of patients with beta-ketothiolase deficiency, propionic acidaemia and methylmalonic acidaemia.
Biomedical Mass Spectrometry 1982;9:1-5.



Elpeleg ON, Meiron D, Barash V, Hurwitz Y, Tal I, Amir N.
3-Methylglutaconic aciduria with persistent metabolic acidosis and 'uncoupling episodes'.
J Inherit Metab Dis 1990;13:235-236.



Elpeleg ON, Costeff H, Joseph A, Shental Y, Weitz R, Gibson KM.
3-Methylglutaconic aciduria in the Iraqi-Jewish 'optic atrophy plus' (Costeff) syndrome.
Dev Med Child Neurol 1994;36:167-172.
Eleven new patients of Iraqi-Jewish origin with bilateral optic atrophy, neurological abnormalities ('optic atrophy plus' syndrome) and 3-methylglutaconic aciduria (type III) are described. Clinical abnormalities in decreasing order of frequency were bilateral optic atrophy, extrapyramidal signs, spasticity, ataxia, dysarthria and cognitive deficit. An association with age was found only for spasticity. Spasticity, extrapyramidal signs and optic atrophy frequently led to major disability, in contrast to ataxia, dysarthria and cognitive deficit. The combined excretion of 3-methylglutaconic and 3-methylglutaric acid ranged between 9 and 187 mmol/mol creatinine. The primary enzymatic defect possibly may reside in the mitochondrial respiratory chain.


Figarella-Branger D, Pellissier JF, Scheiner C, Wernert F, Desnuelle C.
Defects of the mitochondrial respiratory chain complexes in three pediatric cases with hypotonia and cardiac involvement. [Review].
J Neurol Sci 1992;108:105-113.
Three children displaying hypotonia, cardiac involvement and defects of the mitochondrial respiratory chain complexes are reported. The first case showed severe neonatal hypotonia, failure to thrive, hepatomegaly, dilation of the right cardiac cavities, profound lactic acidosis and amino aciduria. The boy died at the age of 7 weeks. In the second case hypotonia, severe cardiomyopathy, cyclic neutropenia, lactic acidosis and 3-methylglutaconic aciduria occurred. The boy died at the age of 27 months. The third case presented at the age of 16 months as an acute hypokinetic hypertrophic cardiomyopathy with transient hypotonia and mild lactic acidosis. Spontaneous clinical remission occurred. In all cases muscle biopsy was performed. Morphological studies failed to show ragged-red fibers but there was lipid storage myopathy and decreased cytochrome c oxidase activity. Biochemical studies confirmed the cytochrome c oxidase deficiency in muscle in all cases. It was associated with complex I III deficiency in case 1 and with severe deficits of all respiratory chain complexes in case 2. Post-mortem studies in case 1 indicated that complex IV was reduced in the liver but not in the heart and quantitative analysis of mtDNA revealed a depletion in muscle. Cases 1 and 2 shared some clinical features with fatal infantile myopathy associated with cytochrome c oxidase deficiency, while case 3 displayed a very unusual clinical presentation. The histochemical enzyme reaction of cytochrome c oxidase is useful for the diagnosis of mitochondrial myopathy because ragged-red fibers may be lacking. Finally, biochemical measurement of the different mitochondrial respiratory chain complexes is required because multiple defects are frequent and occasionally related to mtDNA depletion. [References: 39]


Gedeon AK, Wilson MJ, Colley AC, Sillence DO, Mulley JC.
X linked fatal infantile cardiomyopathy maps to Xq28 and is possibly allelic to Barth syndrome.
J Med Genet 1995;32:383-388.
A number of families with X linked dilated cardiomyopathy with onset in infancy or childhood have now been described, with varying clinical and biochemical features. Of these, one condition, Barth syndrome (BTHS), can be diagnosed clinically by the characteristic associated features of skeletal myopathy, short stature, and neutropenia, but not all of these features are always present. Molecular genetic studies have delineated the gene for BTHS, which maps to distal Xq28, from the gene for so called X linked dilated cardiomyopathy (XLCM), a teenage onset dilated cardiomyopathy, recently mapped to the 5' portion of the dystrophin locus at Xp21. We report a large family in which male infants have died with congenital dilated cardiomyopathy, and there is a strong family history of unexplained death in infant males over at least four generations. Death always occurred in early infancy, without development of the characteristic features associated with Barth syndrome. Molecular analysis localised the gene in this family to Xq28 with lod scores of 2.3 at theta = 0.0 with dinucleotide repeat markers, p26 and p39, near DXS15 and at F8C. The proximal limit to the localisation of the gene in this family is defined by a recombinant at DXS296, while the distal limit could not be differentiated from the telomere. This localisation is consistent with a hypothesis of allelic and clinical heterogeneity at the BTHS locus in Xq28.


Gibson KM.
Assay of 3-methylglutaconyl-CoA hydratase.
Methods in Enzymology 1988;166:214-218.



Gibson KM, Nyhan WL, Sweetman L, Narisawa K, Lehnert W, Divry P, Robinson BH, Roth KS, Beemer FA, van Sprang FJ, et al.
3-Methylglutaconic aciduria: a phenotype in which activity of 3-methylglutaconyl-coenzyme A hydratase is normal.
Eur J Pediatr 1988;148:76-82.
3-Methylglutaconic aciduria has been found in two distinct syndromes. In one there is deficient activity of 3-methylglutaconyl coenzyme A hydratase, and the only clinical manifestation observed has been retardation of speech development. In the other, which includes a majority of the patients studied, we document that the activity of this enzyme in fibroblast extracts is normal. The phenotype of this disorder is one of profound neurological impairment with retarded psychomotor development, hypotonicity and/or spasticity, convulsions or EEG abnormalities, and sensorineural changes in the eye and ear.


Gibson KM, Sherwood WG, Hoffman GF, Stumpf DA, Dianzani I, Schutgens RB, Barth PG, Weismann U, Bachmann C, Schrynemackers-Pitance P, et al.
Phenotypic heterogeneity in the syndromes of 3-methylglutaconic aciduria.
J Pediatr 1991;118:885-890.
Combined 3-methylglutaconic and 3-methylglutaric aciduria, one of the more common urinary organic acid abnormalities, has been observed in at least three clinical syndromes. We studied an additional seven patients with 3-methylglutaconic aciduria, four of whom were best categorized as having the type II syndrome, two as having an "unspecified" syndrome, and one who may have had a primary urea cycle defect. In cultured cells and autopsy tissues derived from patients with the type II and unspecified syndromes, we were unsuccessful in identifying a defect in the leucine degradative pathway distal to 3-methylcrotonyl-coenzyme A carboxylase and in the cholesterol biosynthetic pathway between 3-hydroxy-3-methylglutaryl-coenzyme A reductase and diphosphomevalonate decarboxylase. Further assessment of the cholesterol biosynthetic pathway in several patients with one of the two types of disease also provided no defined abnormality. The primary metabolic defects in the type II and unspecified syndromes remain undefined.


Gibson KM, Lee CF, Wappner RS.
3-Methylglutaconyl-coenzyme-A hydratase deficiency: a new case.
Journal of Inherited Metabolic Disease 1992;15:363-366.



Gibson KM, Bennett MJ, Mize CE, Jakobs C, Rotig A, Munnich A, Lichter-Konecki U, Trefz FK.
3-Methylglutaconic aciduria associated with Pearson syndrome and respiratory chain defects.
J Pediatr 1992;121:940-942.
3-Methylglutaconic aciduria was detected in four patients with Pearson syndrome, a multitissue disorder with hematologic abnormalities, lactic acidosis resulting from defective oxidative phosphorylation, and deletions in the mitochondrial genome. 3-Methylglutaconic acid may be an additional useful marker for Pearson syndrome and may be a more specific marker than other organic acids identified in this disorder.


Gibson KM, Elpeleg ON, Jakobs C, Costeff H, Kelley RI.
Multiple syndromes of 3-methylglutaconic aciduria. [Review].
Pediatr Neurol 1993;9:120-123.
The most common clinical syndromes associated with 3-methylglutaconic aciduria are presented. In some patients these syndromes are multisystemic, progressive disorders of unknown etiology. Tissues deriving significant energy through oxidative metabolism (notably brain and cardiac muscle) are most often affected and in some the primary defect may reside within the mitochondrial respiratory chain. Although increasing biochemical evidence suggests that 3-methylglutaconic aciduria may correlate with deranged mitochondrial energy metabolism, the biochemical origin of 3-methylglutaconic acid and the significance of its increased excretion remain unknown. This review describes these syndromes and illustrates the necessity of urinary organic acid analysis to assist in the differential diagnosis. [References: 17]


Gibson KM, Lee CF, Hoffmann GF.
Screening for defects of branched-chain amino acid metabolism. [Review].
Eur J Pediatr 1994;153:S62-67.
Screening for defects of branched-chain amino acid metabolism is a sequential process involving clinical evaluation of the patient, plasma carnitine determination, urinary organic acid analysis, and enzyme studies in cultured or isolated peripheral cells. This report will summarize clinical and metabolite features and enzymological methods available for the diagnosis of the more common defects of branched-chain amino acid metabolism, including isovaleryl-CoA dehydrogenase deficiency, 3-methylcrotonyl-CoA carboxylase deficiency, 3-methylglutaconic aciduria due to 3-methylglutaconyl-CoA hydratase deficiency and other less well characterized defects, 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, and 2-methylacetoacetyl-CoA thiolase deficiency. Newer enzymatic methodologies utilizing NaH14CO3 fixation coupled assays are described which allow for the estimation of six enzyme activities in the catabolic pathways of L-leucine and L-isoleucine catabolism. These coupled assays facilitate the rapid identification of five of the six enzyme abnormalities described above. Their ease of use should allow them to be implemented in any laboratory which screens for inborn errors of metabolism. [References: 26]


Greter J, Hagberg B, Steen G, Soderhjelm U.
3-methylglutaconic aciduria: report on a sibship with infantile progressive encephalopathy.
European Journal of Pediatrics 1978;129:231-238.



Haan EA, Scholem RD, Pitt JJ, Wraith JE, Brown GK.
Episodes of severe metabolic acidosis in a patient with 3-methylglutaconic aciduria.
Eur J Pediatr 1987;146:484-488.
Persistent excretion of 3-methylglutaconic acid was found in a 6-month-old infant with multiple minor physical malformations and delayed development. During two episodes of intercurrent viral illness, the patient developed severe metabolic acidosis and excreted large amounts of lactate, 3-hydroxybutyrate and acetoacetate. The excretion of 3-methylglutaconic acid did not change during these episodes, nor did it increase following leucine loading. In vitro studies suggest that in this patient, as in the majority of other patients with 3-methylglutaconic aciduria, a primary defect in leucine metabolism is not responsible for the biochemical abnormality.


Hagberg B, Hjalmarson O, Lindstedt S, Ransnas L, Steen G.
3-Methylglutaconic aciduria in two infants.
Clinica Chimica Acta 1983;134:59-67.



Hammond J, Wilcken B.
3-hydroxy-3-methylglutaric, 3-methylglutaconic and 3-methylglutaric acids can be non-specific indicators of metabolic disease.
J Inherit Metab Dis 1984;2:117-118.



Heiss NS, Rogner UC, Kioschis P, Korn B, Poustka A.
Transcription mapping in a 700-kb region around the DXS52 locus in Xq28: isolation of six novel transcripts and a novel ATPase isoform (hPMCA5).
Genome Res 1996;6:478-491.
The chromosomal band Xq28 has been a focus of interest in human genetics because > 20 hereditary diseases have been mapped to this region. However, about two-thirds of the disease genes remain uncloned. The region around the polymorphic DXS52 locus (ST14) within Xq28 lies in the candidate regions for several as-yet-uncloned disease genes. So far, only four melanoma antigen genes (MAGE) and the human biglycan (BGN) gene, have been mapped within the 700-kb stretch around DXS52, suggesting that more genes may reside in this region. By combining exon trapping and direct cDNA selection methods, we sought to identify novel transcripts around the DXS52 locus. In addition to recovering the MAGE and BGN genes, we isolated and mapped six putative novel genes (XAP103-XAP108), the caltractin gene, and a gene encoding a novel Ca(2+)-transporting ATPase isoform (hPMCA5). The newly isolated sequences were considered as representing parts of putative genes if they contained at least one unique exon-trap product and/or at least one expressed sequence tag (EST) from sequence data bases and if, in addition, they showed evidence of expressed RT-OCT and/or Northern blot analysis. Our data facilitated the integration of the transcription map with the physical map around the DXS52 locus. Future analysis of the novel genes as candidates for Barth syndrome (BTHS) and chondrodysplasia punctata (CDPX2) is in progress.


Holme E, Greter J, Jacobson CE, Larsson NG, Lindstedt S, Nilsson KO, Oldfors A, Tulinius M.
Mitochondrial ATP-synthase deficiency in a child with 3-methylglutaconic aciduria.
Pediatr Res 1992;32:731-735.
We report the finding of mitochondrial ATP-synthase deficiency in a child with persistent 3-methylglutaconic aciduria. The child presented in the neonatal period with severe lactic acidosis, which was controlled by Na-HCO3 and glucose infusions. During the 1st y of life, there were several episodes of lactic acidosis precipitated by infections or prolonged intervals between meals. The excretion of lactate in urine was variable, but there was a persistent high excretion of 3-methylglutaconic acid. The activity of 3-methylglutaconyl-CoA hydratase in fibroblasts was normal. The child had a hypertrophic cardiomyopathy and magnetic resonance images revealed hypoplasia of corpus callosum. The gross motor and mental development was retarded, but there were no other neurologic signs. Investigation of muscle mitochondrial function at 1 y of age revealed a severe mitochondrial ATP-synthase deficiency (oligomycin-sensitive, dinitrophenol-stimulated Mg2+ ATPase activity: 27 nmol x min-1 x (mg protein)-1, control range 223-673 nmol x min-1 x (mg protein)-1. The mitochondrial respiratory rate was low and tightly coupled. The respiratory rate was normalized by the addition of an uncoupler. Low Mg2+ ATPase activity was also demonstrated by histochemical methods. Morphologic examination revealed ultrastructural abnormalities of mitochondria. There was no deletion of mitochondrial DNA. The sequences of the ATP synthase subunit genes of mitochondrial DNA were in accordance with published normal sequences.


Hou JW, Wang TR.
3-Methylglutaconic aciduria presenting as Reye syndrome in a Chinese boy.
J Inherit Metab Dis 1995;18:645-646.



Ibel H, Endres W, Hadorn HB, Deufel T, Paetzke I, Duran M, Kennaway NG, Gibson KM.
Multiple respiratory chain abnormalities associated with hypertrophic cardiomyopathy and 3-methylglutaconic aciduria.
Eur J Pediatr 1993;152:665-670.
In a 4.5-month-old boy presenting with marked muscular hypotonia in the neonatal period, hepatomegaly, cardiac hypertrophy, recurrent hypoglycemia, metabolic acidosis, and secondary carnitine deficiency, there was a considerable urinary excretion of 3-methylglutaconic and 3-methylglutaric acid. Estimation of 3-methylglutaconyl-CoA hydratase, 3-hydroxy-3-methylglutaryl-CoA lyase and initial enzymatic steps of cholesterol biosynthesis in cultured fibroblasts and in different tissues postmortem revealed no enzyme deficiency. Analyses of the respiratory chain in postmortem tissues demonstrated severe impairment of complex I (NADH ubiquinone oxidoreductase) and complex IV (cytochrome c oxidase) activities in skeletal muscle and reduced complex IV activity in heart.


Ino T, Sherwood WG, Cutz E, Benson LN, Rose V, Freedom RM.
Dilated cardiomyopathy with neutropenia, short stature, and abnormal carnitine metabolism [see comments].
Journal of Pediatrics 1988;113:511-514.



Ino T, Sherwood WG, Benson LN, Wilson GJ, Freedom RM, Rowe RD.
Cardiac manifestations in disorders of fat and carnitine metabolism in infancy.
Journal of the American College of Cardiology 1988;11:1301-1308.



Itokawa Y.
[Trace elements in long-term total parenteral nutrition]. [Review] [Japanese].
Nippon Rinsho 1996;54:172-178.
Deficiency symptoms of trace elements developed in patients receiving long-term total parenteral nutrition (TPN) are as follows. [Zinc deficiency]: moist eczematoid dermatitis and alopetia are occurred in patients receiving TPN which not containing zinc. Plasma zinc level was very low. The response to intravenous zinc therapy is striking. [Copper deficiency]: anemie and neutropenia caused in patients receiving TPN which not containing copper. These abnormalities disappeared after copper therapy. [Manganese deficiency]: bone changes which thought to be due to manganese deficiency was observed in patient receiving TPN. [Selenium deficiency]: dilated cardiomyopathy resembles to Keshan disease was occurred in patients receiving TPN for long term. [Chromium deficiency]: TPN induced chromium deficiency developed characterized by peripheral neuropathy and glucose intolerance. [Molybudenum deficiency]: Amino acid intolerance due to molybudenum deficiency is occurred in patients receiving TPN. Requirement of trace elements for human adults from TPN estimated as follows. zinc: 3-4 mg/day, copper: 0.02-0.05 mg/day, iron: 1-2 mg/day, manganese: 0.15-0.80 mg/day, selenium: 0.02-0.05 mg/day, chromium: 0.01-0.015 mg/day, molybudenum: 0.075-0.250 mg/day and iodine: 0.070-0.140 mg/day. [References: 20]


Jooste S, Erasmus E, Mienie LJ, de Wet WJ, Gibson KM.
The detection of 3-methylglutarylcarnitine and a new dicarboxylic conjugate, 3-methylglutaconylcarnitine, in 3-methylglutaconic aciduria.
Clin Chim Acta 1994;230:1-8.
Two patients, diagnosed with 3-methylglutaconic aciduria, who presented with diverse clinical and metabolic manifestations, were studied. Glycine conjugation as a possible detoxification mechanism in these two patients yielded negative results. Carnitine conjugates were however detected. 3-Methylglutarylcarnitine was observed in the urine of both patients, while one of the patients excreted detectable quantities of 3-methylglutaconylcarnitine, a previously unknown metabolite. The presence of this metabolite in urine samples from one patient and the apparent correlation between administered carnitine and the conjugate excretion profile seems to indicate that carnitine may play an important role in future therapeutic programmes.


Kelley RI, Cheatham JP, Clark BJ, Nigro MA, Powell BR, Sherwood GW, Sladky JT, Swisher WP.
X-linked dilated cardiomyopathy with neutropenia, growth retardation, and 3-methylglutaconic aciduria.
J Pediatr 1991;119:738-747.
Seven boys with an apparently X-linked syndrome of dilated cardiomyopathy, growth retardation, neutropenia, and persistently elevated urinary levels of 3-methylglutaconate, 3-methylglutarate, and 2-ethylhydracrylate were studied. The natural history of the disorder was characterized by severe or lethal cardiac disease and recurrent infections during infancy and early childhood but relative improvement in later childhood. The initial presentation of the syndrome varied from congenital dilated cardiomyopathy to infantile congestive heart failure to isolated neutropenia without clinical evidence of heart disease. The excretion of 3-methylglutaconate and 3-methylglutarate appeared to be independent of the metabolism of leucine, the presumed precursor of these organic acids in humans. Although the cause of the organic aciduria remains obscure, the constellation of biochemical and clinical abnormalities forms a distinct syndrome that may be a relatively common cause of dilated cardiomyopathy or neutropenia in boys during infancy and childhood.


Kelley RI.
Quantification of 3-methylglutaconic acid in urine, plasma, and amniotic fluid by isotope-dilution gas chromatography/mass spectrometry.
Clin Chim Acta 1993;220:157-164.
A method is described for quantification of the trace metabolite, 3-methylglutaconic acid, by isotope-dilution gas chromatography/mass spectrometry using synthetic 3-[2,4,6-13C3]methylglutaconic acid. Results are shown for quantification of 3-methylglutaconic acid in plasma, urine, cerebrospinal fluid and amniotic fluid for both normal controls and patients with different forms of 3-methylglutaconic aciduria. A simple method for the synthesis and purification of 3-[2,4,6-13C3]methylglutaconic acid is also described.


Kelley RI, Kratz L.
3-methylglutaconic acidemia in Smith-Lemli-Opitz syndrome.
Pediatr Res 1995;37:671-674.
The branched-chain organic acid, 3-methylglutaconic acid, is an intermediate (as the CoA thioester) in the leucine degradative pathway as well as the mevalonate shunt, a pathway that links isoprenoid metabolism with mitochondrial acetyl-CoA metabolism. Because the majority of patients with abnormal 3-methylglutaconic aciduria or acidemia appear to have normal leucine metabolism, we have speculated that some patients with 3-methylglutaconic aciduria may have defects of polyisoprenoid or sterol biosynthesis leading to overflow of isoprenoid precursors to 3-methylglutaconate via the mevalonate shunt. We therefore measured plasma levels of 3-methylglutaconic acid in patients with a known defect of sterol biosynthesis, Smith-Lemli-Opitz syndrome, and found that the patients with the lowest cholesterol levels had abnormally increased plasma levels of 3-methylglutaconic acid, similar in magnitude to those of patients with idiopathic 3-methylglutaconic aciduria. This finding suggests that some patients with unexplained 3-methylglutaconic aciduria may have defects of isoprenoid or sterol biosynthesis underlying their abnormal organic aciduria.


Kesler A, Gadoth N, Straussberg R.
3-Methylglutaconic aciduria: a new metabolic disorder associated with early onset optic atrophy [letter].
J Neuroophthalmol 1997;17:278-279.



Kuhara T, Shinka T, Matsuo M, Matsumoto I.
Increased excretion of lactate, glutarate, 3-hydroxyisovalerate and 3-methylglutaconate during clinical episodes of propionic acidemia.
Clinica Chimica Acta 1982;123:101-109.



Kuhara T, Matsumoto I, Saiki K, Takabayashi H, Kuwabara S.
3-Methylglutaconic aciduria in two adults [letter].
Clin Chim Acta 1992;207:151-153.



Largilliere C, Vallee L, Cartigny B, Dubos JP, Gibson KM, Nuyts JP, Farriaux JP.
3-Methylglutaconic aciduria: neonatal onset with lactic acidosis.
J Inherit Metab Dis 1989;12:333-334.



Lehnert W, Scharf J, Wendel U.
3-Methylglutaconic and 3-methylglutaric aciduria in a patient with suspected 3-methylglutaconyl-CoA hydratase deficiency.
Eur J Pediatr 1985;143:301-303.
A girl suffering from marked muscular hypotonia, severe statomotor and mental retardation, bilateral optic atrophy with chorioretinal degeneration, convulsions and a moderate compensated metabolic acidosis is described. Screening for metabolic disorders revealed massive 3-methylglutaconic with 3-methylglutaric aciduria leading to the tentative diagnosis of 3-methylglutaconyl-CoA hydratase deficiency. Metabolite excretion was correlated with variation of leucine intake. 3-methyl-3-hydroxyglutaryl-CoA lyase activity in cultured fibroblasts was normal. The suspected metabolic defect was not demonstrable in cultured skin fibroblasts, however.


Lichter-Konecki U, Trefz FK, Rotig A, Munnich A, Pfeil A, Bremer HJ.
3-Methylglutaconic aciduria in a patient with Pearson syndrome [letter].
Eur J Pediatr 1993;152:378.



Liebich HM, Pickert A, Stierle U, Woll J.
Gas chromatography-mass spectrometry of saturated and unsaturated dicarboxylic acids in urine.
Journal of Chromatography 1980;199:181-189.



Lynen F.
[A new method of preparation of methylglutaconase from ox liver]. [French].
Comptes Rendus Hebdomadaires des Seances de l Academie des Sciences - D: Sciences Naturelles 1970;270:3318-3320.



Milasin J, Muntoni F, Severini GM, Bartoloni L, Vatta M, Krajinovic M, Mateddu A, Angelini C, Camerini F, Falaschi A, Mestroni L, Giacca M.
A point mutation in the 5' splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy.
Hum Mol Genet 1996;5:73-79.
X-linked dilated cardiomyopathy (XLDC) is a familial heart disease presenting in young males as a rapidly progressive congestive heart failure, without clinical signs of skeletal myopathy. This condition has recently been linked to the dystrophin gene in some families and deletions encompassing the genomic region coding for the first muscle exon have been detected. In order to identify the defect responsible for this disease at the molecular level and to understand the reasons for the selective heart involvement, a family with a severe form of XLDC was studied. In the affected members, no deletions of the dystrophin gene were observed. Analysis of the muscle promoter, first exon and intron regions revealed the presence of a single point mutation at the first exon-intron boundary, inactivating the universally conserved 5' splice site consensus sequence of the first intron. This mutation introduced a new restriction site for MseI, which cosegregates with the disease in the analyzed family. Expression of the major dystrophin mRNA isoforms (from the muscle-, brain- and Purkinje cell-promoters) was completely abolished in the myocardium, while the brain- and Purkinje cell- (but not the muscle-) isoforms were detectable in the skeletal muscle. Immunocytochemical studies with anti-dystrophin antibodies showed that the protein was reduced in quantity but normally distributed in the skeletal muscle, while it was undetectable in the cardiac muscle. These findings indicate that expression of the muscle dystrophin isoform is critical for myocardial function and suggest that selective heart involvement in dystrophin-linked dilated cardiomyopathy is related to the absence, in the heart, of a compensatory expression of dystrophin from alternative promoters.


Mitchell GA, Jakobs C, Gibson KM, Robert MF, Burlina A, Dionisi-Vici C, Dallaire L.
Molecular prenatal diagnosis of 3-hydroxy-3-methylglutaryl CoA lyase deficiency.
Prenat Diagn 1995;15:725-729.
We report the first molecular prenatal diagnosis of 3-hydroxy-3-methylglutaryl CoA lyase (HL) deficiency. The proband had a classic but severe presentation with hypoketotic hypoglycaemia and acidosis, secondary mental retardation, and epilepsy, and HL deficiency was documented in cultured fibroblasts. We found him to be homozygous for the frameshift mutation N46fs (+1), which yields a distinct pattern on single-strand conformation polymorphism (SSCP) analysis. In two subsequent pregnancies, molecular prenatal diagnosis was performed using SSCP. In the first, chorionic villus biopsy was normal. In the second pregnancy, amniocentesis revealed an affected fetus. In both pregnancies, the diagnosis was confirmed enzymatically. HL activity was less than 7 per cent of control values in amniocytes and fetal liver of the affected pregnancy. In the second pregnancy, amniotic fluid metabolite measurements by stable isotope dilution-selected ion monitoring mass spectrometry showed greater than 100-fold increases of 3-hydroxy-3-methylglutaric acid and of 3-methylglutaconic acid levels compared with controls.


Narisawa K, Gibson KM, Sweetman L, Nyhan WL, Duran M, Wadman SK.
Deficiency of 3-methylglutaconyl-coenzyme A hydratase in two siblings with 3-methylglutaconic aciduria.
J Clin Invest 1986;77:1148-1152.
We studied two patients with 3-methylglutaconic aciduria in order to determine the molecular defect. A new assay for 3-methylglutaconyl-coenzyme A (CoA) hydratase has been developed in which the substrate, [5-14C]3-methylglutaconyl-CoA, was synthesized using 3-methylcrotonyl-CoA carboxylase purified from bovine kidney. In this assay the products of the reaction are isolated by reverse-phase high performance liquid chromatography and the rates of conversion from substrate are measured. The Michaelis constant for 3-methylglutaconyl-CoA in normal fibroblasts was 6.9 mumol/liter. The mean activity of 3-methylglutaconyl-CoA hydratase in control fibroblasts was 495 pmol/min per mg protein. In the two patients the values were 11 and 17 pmol/min per mg protein, or 2-3% of normal.


Narisawa K, Gibson KM, Sweetman L, Nyhan WL.
3-Methylglutaconyl-CoA hydratase, 3-methylcrotonyl-CoA carboxylase and 3-hydroxy-3-methylglutaryl-CoA lyase deficiencies: a coupled enzyme assay useful for their detection.
Clinica Chimica Acta 1989;184:57-64.



Netter JC, Divry P, Delisle B, Bildstein G, Andrieu A, Laurent-Pellegrin M, Chateauneuf R, Petrus M.
[Hypertrophic cardiomyopathy and neonatal encephalopathy associated with 3-methylglutaconic aciduria]. [French].
Ann Pediatr 1987;34:741-742.



Norman EJ, Denton MD, Berry HK.
Gas-chromatographic/mass spectrometric detection of 3-hydroxy-3-methylglutaryl-CoA lyase deficiency in double first cousins.
Clinical Chemistry 1982;28:137-140.



Nystuen A, Costeff H, Elpeleg ON, Apter N, Bonne-Tamir B, Mohrenweiser H, Haider N, Stone EM, Sheffield VC.
Iraqi-Jewish kindreds with optic atrophy plus (3-methylglutaconic aciduria type 3) demonstrate linkage disequilibrium with the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene.
Hum Mol Genet 1997;6:563-569.
Iraqi-Jewish optic atrophy plus is an autosomal recessive condition characterized by infantile optic atrophy, an early onset movement disorder, and 3-methylglutaconic aciduria. Other features include spastic paraplegia, mild ataxia, mild cognitive deficiency and dysarthria. This disorder was identified in inbred Iraqi-Jewish kindreds in which relationships between most of the affected individuals were unknown. In this study we identify linkage to chromosome 19q13.2-q13.3 by using a DNA pooling strategy to perform a genome wide screen followed by a high density search for shared segments among affected individuals in candidate regions identified in the initial genome wide screen. A significantly high positive lod score of 6.14 at zero recombination was obtained for the CTG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase gene. The existence of multiple recombinant individuals indicates the disease interval can be further narrowed with additional markers. Linkage disequilibrium was seen in six polymorphic markers across a 1 Mb interval. This region is well characterized and contains several candidate genes.


Oldfors A, Eriksson BO, Kyllerman M, Martinsson T, Wahlstrom J.
Dilated cardiomyopathy and the dystrophin gene: an illustrated review. [Review].
Br Heart J 1994;72:344-348.
Cardiomyopathy is often found in patients with Duchenne and Becker muscular dystrophy, which are X linked muscle diseases caused by mutations in the dystrophin gene. Dystrophin defects present in many different ways and cases of mild Becker muscular dystrophy have been described in which cardiomyopathy was severe. Female carriers of Duchenne muscular dystrophy can develop symptomatic skeletal myopathy alone or combined with dilated cardiomyopathy. They can also develop dilated cardiomyopathy alone. X linked dilated cardiomyopathy has been found in association with dystrophin defects. The relation between the molecular defects and the cardiac phenotypes has not yet been established. New mutations in the dystrophin gene are common and such mutations cause one third of the cases with Duchenne and Becker muscular dystrophy. This means that sporadic cases of cardiomyopathy caused by dystrophin defects are likely. This paper reports such a case in a boy of 14 who died of dilated cardiomyopathy. Before the cardiac investigation, which was performed one month before he died, he had not complained of muscular weakness. He had minor signs of limb girdle myopathy and slightly increased concentrations of serum creatine kinase. He was found to have an unusual deletion in the dystrophin gene. [References: 39]


Orstavik KH, Skjorten F, Hellebostad M, Haga P, Langslet A.
Possible X linked congenital mitochondrial cardiomyopathy in three families.
J Med Genet 1993;30:269-272.
Familial cases of childhood congestive cardiomyopathy with X linked recessive inheritance and abnormalities of heart muscle mitochondria have been previously reported. We report here three families with possible X linked congestive cardiomyopathy and specific mitochondrial abnormalities. The heart disorder presented as endocardial fibroelastosis with neonatal death in two brothers in one family, and as heart failure and death in infancy in two brothers in the other two families. In one family a maternal uncle may also have been affected. Pyodermia and neutropenia was reported in one of the boys. Electron microscopy of heart muscle after necropsy showed increased numbers of mitochondria and abnormal mitochondrial crystal condensations and paracrystalline inclusions in all sibships. Barth's syndrome has been mapped to Xq28 and includes cardiomyopathy, skeletal muscle myopathy, neutropenia, and mitochondrial abnormalities similar to those found in the three families reported here. Since the clinical picture differed in the three families, they may represent more than one entity.


Ostman-Smith I, Brown G, Johnson A, Land JM.
Dilated cardiomyopathy due to type II X-linked 3-methylglutaconic aciduria: successful treatment with pantothenic acid.
Br Heart J 1994;72:349-353.
A case of dilated cardiomyopathy in a young boy secondary to type II 3-methylglutaconic aciduria is described. A metabolic cause for his dilated cardiomyopathy was suspected because of the development on the electrocardiogram of an unusual "camel's hump" shape of the T waves, and of progressive thickening with increasing echogenicity of the left ventricular wall. He initially improved on digoxin treatment, but did not maintain the response with conventional dietary treatment for this condition. Supplementation with L-carnitine was associated with rapid deterioration in cardiac state, and may be contraindicated in this condition. At a point when the patient was moribund, large doses of pantothenic acid, a precursor of coenzyme A, produced a dramatic and sustained improvement in myocardial function and in growth, neutrophil cell count, hypocholesterolaemia, and hyperuricaemia, which suggests that limitation of availability of coenzyme A is a fundamental pathological process in this condition. The clinical improvement has been maintained for 13 months, and myocardial function is now nearly normal. Oral pantothenol, unlike pantothenic acid, is not efficacious.


Page T, Nyhan WL.
Separation of the intermediates of leucine catabolism by high-performance liquid chromatography.
Biochemical Medicine 1985;34:297-303.



Parrish JE, Ciccodicola A, Wehhert M, Cox GF, Chen E, Nelson DL.
A muscle-specific DNase I-like gene in human Xq28.
Hum Mol Genet 1995;4:1557-1564.
A novel cDNA which maps to human Xq28 has been isolated and characterized. Sequence similarity to DNase I is high at the DNA and peptide sequence levels. The transcript is present at highest levels in skeletal and cardiac muscle, with lower expression in other tissues. Mutation analysis has been performed using DNA samples from two unrelated patients with Barth syndrome, and from 11 unrelated patients with Emery-Dreifuss muscular dystrophy, two genetic disorders linked to Xq28. No disease-associated mutations were detected in the coding region of the gene; however, a novel 190 base pair insertion/deletion polymorphism was found in the 3' untranslated region. Translation of the long open reading frame found in the cDNA yields a putative 302 amino acid protein with 37.6% identity to human DNase I. The protein is predicted to contain a signal sequence at the amino terminus, a transmembrane domain near the carboxyl terminus, and a helix-loop-helix domain.


Robinson BH, Oei J, Sherwood WG, Slyper AH, Heininger J, Mamer OA.
Hydroxymethylglutaryl CoA lyase deficiency: features resembling Reye syndrome.
Neurology 1980;30:714-718.



Roe CR, Millington DS, Maltby DA.
Identification of 3-methylglutarylcarnitine. A new diagnostic metabolite of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency.
Journal of Clinical Investigation 1986;77:1391-1394.



Roubicek M.
X-linked dilated cardiomyopathy [letter; comment].
N Engl J Med 1994;330:370.



Ruitenbeek W, Wendel U, Hamel BC, Trijbels JM.
Genetic counselling and prenatal diagnosis in disorders of the mitochondrial energy metabolism. [Review] [33 refs].
J Inherit Metab Dis 1996;19:581-587.
Point mutations in mitochondrial DNA, as found in MELAS, MERRF, NARP and other syndromes, are inherited via the maternal lineage. Genetic counselling can be beneficial, but prenatal diagnosis is not advantageous in these syndromes. Empirical data about the recurrence risk can be applied in Leber disease (LHON). Mitochondrial disorders not associated with a point mutation have a sporadic nature (large deletions/duplications in mitochondrial DNA) or are transmitted according to Mendelian laws. Autosomal dominant inheritance is likely to be found in disorders with depletion of mitochondrial DNA. X-linked mode of inheritance is seen in Menkes disease, Barth syndrome, and in deficiencies of the E1 alpha subunit of the pyruvate dehydrogenase complex. Mutation analysis or linkage studies can be applied for carrier detection and prenatal diagnosis in these three types of mitochondriopathies. The majority of the disorders with a disturbed mitochondrial energy metabolism are likely inherited in an autosomal recessive mode. Prenatal diagnosis can be performed in the cases of cytochrome c oxidase and NADH dehydrogenase deficiencies in chorionic villi in selected families. [References: 33]


Schwabauer RA, Li CH, Adams GS, Gamble W.
Utilization of mevalonate by aorta for the synthesis of medium-chain n-fatty acids (C8, C10) and acylglycerols.
Biochimica et Biophysica Acta 1988;960:139-147.



Sheffer RN, Zlotogora J, Elpeleg ON, Raz J, Ben-Ezra D.
Behr's syndrome and 3-methylglutaconic aciduria.
Am J Ophthalmol 1992;114:494-497.
We examined three patients from two families of Jewish-Iraqi origin who had progressive reduction of visual acuity and childhood onset of bilateral optic nerve atrophy without additional retinal abnormalities. They had neurologic symptoms compatible with Behr's syndrome. Neurologic signs included increased tendon reflexes, a positive Babinski sign, progressive spastic paraplegia, dysarthria, head nodding, and horizontal nystagmus. Neurologic involvement varied between affected siblings. The patients excreted excessive amounts of 3-methylglutaconic acid and 3-methylglutaric acid in their urine. We compared the characteristic ophthalmic features and the spectrum of neurologic signs encountered in this recently delineated autosomal recessive clinical entity with those of previously described entities associated with 3-methylglutaconic aciduria. Patients with early-onset optic atrophy should be examined for neurologic signs and screened for organic aciduria. A detailed ophthalmic examination is important in patients with neurologic abnormalities compatible with Behr's syndrome.


Shinka T, Kuhara T, Inoue Y, Matsumoto M, Matsumoto I, Nakamura H, Irimichi H, Hasumi K, Endo A.
GC/MS analysis of urine in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency.
Acta Paediatr Jpn 1992;34:157-165.
A patient with 3-hydroxy-3-methylglutaric aciduria was diagnosed using gas chromatography mass spectrometry. The patient had severe metabolic acidosis, hypoglycemia and hyperammonemia and excreted abnormal amounts of 3-methylglutaconic, 3-hydroxy-3-methylglutaric, 3-methylglutaric, 3-hydroxyisovaleric and glutaric acids in the urine. 3-Hydroxy-3-methylglutaric acid appeared as two peaks on the chromatogram after trimethylsilylation. One was a tri-trimethylsilyl and the other a di-trimethylsilyl derivative. 3-Methylglutaconic acid appeared as three peaks: cis-, trans- and cyclic cis-isomers. The structure of these derivatives was elucidated by deuterium-labeled trimethylsilyl derivatization. The di-trimethylsilyl derivative of 3-hydroxy-3-methylglutaric acid and the cyclic cis-isomer of 3-methylglutaconic acid do not appear to have been previously described. After treatment with leucine restriction milk, the excretion of leucine catabolites decreased but 3-methylglutaconic and 3-hydroxy-3-methylglutaric acids continued to be excreted at abnormally high levels. It is concluded that these two metabolites are necessary for the chemical diagnosis of HMG-CoA lyase deficiency. This patient is the first case of HMG-CoA lyase deficiency to be reported in Japan.


Steen G, Ransnas L.
Organic acids or urine in multiple sclerosis.
Acta Neurologica Scandinavica 1983;68:231-240.



Steen G, Axelsson H, Bowallius M, Holthuis N, Molander BM.
Isoprenoid biosynthesis in multiple sclerosis, II. A possible role of NADPH.
Acta Neurol Scand 1987;76:461-467.
Genetic predisposition in MS, influence of fat consumption on the disease, and excretion of lipid metabolites in urine led us to investigate isoprenoid metabolism in this disease. Ubiquinone concentration and biosynthesis was normal in lymphocytes. Cytochrome oxidase, which contains an isoprenoid side chain, was normal in activity. Cholesterol biosynthesis from acetate was found to be elevated in MS, and so was triglyceride biosynthesis. Increased biosynthesis may offer a very simple explanation to all the metabolites excreted (3-methylglutaconic acid, 2-hydroxy-2-methyl-3-butenoic acid and adipic acid). Increased biosynthesis may be caused by an elevated NADPH/NADP ratio, since such an elevation may also account for many other biochemical anomalies in MS. Elevated NADPH/NADP ratio may be of direct importance in the pathogenesis.


Towbin JA.
Molecular genetic aspects of cardiomyopathy. [Review].
Biochem Med Metab Biol 1993;49:285-320.
Cardiomyopathies are a major cause of mortality and morbidity and this spectrum of disorders tops the list of diseases leading to cardiac transplantation. While significant gains have been made during the past decade clinically, knowledge of the molecular aspects of these disorders has taken longer to advance. During the past 5 years, however, molecular genetic information on a variety of primary cardiomyopathies, such as familial hypertrophic cardiomyopathy and X-linked dilated cardiomyopathy, has been obtained. Other primary and secondary myocardial diseases are now under study with advances occurring more regularly. The purpose of this review is to outline the major advances thus far described for some primary and secondary cardiomyopathies, as well as detailing the slower progress seen for others. [References: 149]


Towbin JA, Hejtmancik JF, Brink P, Gelb B, Zhu XM, Chamberlain JS, McCabe ER, Swift M.
X-linked dilated cardiomyopathy. Molecular genetic evidence of linkage to the Duchenne muscular dystrophy (dystrophin) gene at the Xp21 locus.
Circulation 1993;87:1854-1865.
BACKGROUND. X-linked cardiomyopathy (XLCM) is a rapidly progressive primary myocardial disorder presenting in teenage males as congestive heart failure. Manifesting female carriers have later onset (fifth decade) and slower progression. The purpose of this study was to localize the XLCM gene locus in two families using molecular genetic techniques. METHODS AND RESULTS. Linkage analysis using 60 X-chromosome-specific DNA markers was performed in a previously reported large XLCM pedigree and a smaller new pedigree. Two-point and multipoint linkage was calculated using the LINKAGE computer program package. Deletion analysis included multiplex polymerase chain reaction (PCR). Dystrophin protein was evaluated by Western blotting with N-terminal and C-terminal dystrophin antibody. Linkage of XLCM to the centromeric portion of the dystrophin or Duchenne muscular dystrophy (DMD) locus at Xp21 was demonstrated with combined maximum logarithm of the scores of +4.33, theta = 0 with probe XJ1.1 (DXS206) using two-point linkage and +4.81 at XJ1.1 with multipoint linkage analysis. LOD scores calculated using other proximal DMD genomic and cDNA probes and polymerase chain reaction polymorphisms supported linkage. No deletions were observed. Abnormalities of cardiac dystrophin were shown by Western blotting with N-terminal dystrophin antibody, whereas skeletal muscle dystrophin was normal, suggesting primary involvement of the DMD gene with preferential involvement of cardiac muscle. CONCLUSIONS. XLCM is due to an abnormality within the centromeric half of the dystrophin genomic region in heart. This abnormality could be due to 1) a point mutation in the 5' region of the DMD coding sequence preferentially affecting cardiac function, 2) a cardiac-specific promoter mutation that alters expression in this tissue, 3) splicing abnormalities, resulting in an abnormal cardiac protein, or 4) deletion mutations undetectable by Southern and multiplex polymerase chain reaction analysis.


Vakkuri P, Airaksinen E, Karttunen P, Ollikainen J, Paakkonen L, Ruostesuo J, Ruotsalainen H, Ruokonen A.
[3-Methylglutaconic aciduria]. [Finnish].
Duodecim 1987;103:87-91.



Wadman SK, Duran M, Kamerling JP.
Organic acidurias: approach, results and clinical relevance.
Ciba Foundation Symposium 1982;87:324-339.



Worthen HG, al Ashwal A, Ozand PT, Garawi S, Rahbeeni Z, al Odaib A, Subramanyam SB, Rashed M.
Comparative frequency and severity of hypoglycemia in selected organic acidemias, branched chain amino acidemia, and disorders of fructose metabolism.
Brain Dev 1994;16:81-85.
The Institution's experience with hypoglycemia in different types of organic acidemias, branched chain amino acidemia (MSUD), and disorders of fructose metabolism was reviewed retrospectively. The charts of 144 patients who were followed for 1-5 years were studied for the severity and frequency of hypoglycemia. The patients were mainly Saudi; however, 10-25% were from neighboring countries. Therefore, the observations pertain to the genetic groups in the Arabian peninsula. Organic acidemias which primarily manifest with neurologic signs, such as 4-hydroxybutyric aciduria, infantile onset 3-methylglutaconic aciduria, and glutaric aciduria type 1 never showed hypoglycemia. Patients with beta-ketothiolase deficiency, biotinidase deficiency, or intermittent or intermediate MSUD, also did not have hypoglycemia during metabolic crisis. Hypoglycemia was rare and mild among neonates with classic MSUD, ethylmalonic aciduria, and isovaleric acidemia. Less than 50% of the patients with MSUD older than 8 months, pyruvate carboxylase deficiency, methylmalonic acidemia, or propionic acidemia had hypoglycemia during metabolic crisis. On the other hand, patients with 3-hydroxy-3-methyl glutaryl-CoA lyase deficiency, holocarboxylase synthetase deficiency, medium or long-chain acyl-CoA dehydrogenase deficiency, neonatal onset 3-methylglutaconic aciduria, glutaric aciduria type 2, and disorders of fructose metabolism invariably had moderate-to-severe hypoglycemia associated with metabolic crisis. The purpose of this report is to provide the pediatrician, particularly in the Middle East, with a diagnostic guideline to the identification and management of different types of organic acidemias, based on co-existing hypoglycemia.


Wysocki SJ, Wilkinson SP, Hahnel R, Wong CY, Panegyres PK.
3-Hydroxy-3-methylglutaric aciduria, combined with 3-methylglutaconic aciduria.
Clinica Chimica Acta 1976;70:399-406.



Yoshida I, Sovik O, Sweetman L, Nyhan WL.
Metabolism of leucine in fibroblasts from patients with deficiencies in each of the major catabolic enzymes: branched-chain ketoacid dehydrogenase, isovaleryl-CoA dehydrogenase, 3-methylcrotonyl-CoA carboxylase, 3-methylglutaconyl-CoA hydratase, and 3-hydroxy-3-methylglutaryl-CoA lyase.
Journal of Neurogenetics 1985;2:413-424.



Yoshida I.
[Methylglutaconic aciduria (normal hydratase, unspecified)].
Ryoikibetsu Shokogun Shirizu 1998:295-298.



Yoshida I.
[X-linked 3-methylglutaconic aciduria (normal hydratase)].
Ryoikibetsu Shokogun Shirizu 1998:292-294.



Yoshida I.
[3-Methylglutaconyl-CoA hydratase deficiency].
Ryoikibetsu Shokogun Shirizu 1998:288-291.



Zeharia A, Elpeleg ON, Mukamel M, Weitz R, Ariel R, Mimouni M.
3-Methylglutaconic aciduria: a new variant.
Pediatrics 1992;89:1080-1082.
3-Methylglutaconic aciduria has been described in two distinct syndromes. In one there was deficient 3-methylglutaconyl coenzyme A hydratase in fibroblast extracts where the only clinical manifestation was retarded speech development. In the second syndrome, the enzyme activity was normal but prominent neurological deterioration was noted. We describe two siblings with 3-methylglutaconic aciduria with normal enzyme activity who had choreoathetoid movements, optic atrophy, and mild developmental delay. The boy demonstrated developmental improvement in his second year of life, and his sister developed well, with normal school performance. These patients represent a new clinical variant of the second syndrome with a relatively favorable prognosis.