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MRI and MRS in HMG-CoA lyase deficiency
MRI and MRS in HMG-CoA Lyase Deficiency Cengiz Yalc¸ınkaya, MD*, Alp Dinc¸er, MD†, Erem Gu¨ndu¨z, MD*, Can Fıc¸ıcıog˘lu, MD‡, Naci Koc¸er, MD§, and Ahmet Aydın‡ 3-Hydroxy-3-Methylglutaryl coenzyme A lyase (HMGCoA) deficiency is a rare inborn error of leucine catabolism. The disease is characterized by recurrent episodes of metabolic acidosis, hyperammonemia without ketosis, hypoglycemia, lethargy, hepatomegaly, and seizures. This study has evaluated the magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) findings of three patients with HMGCoA deficiency. The common findings on all of the MRI scans were multiple, coalescent, marked lesions in periventricular white matter and arcuate fibers, most prominently in frontal or periatrial regions that were superimposed on diffuse, slightly hyperintense subcortical white matter signal. Involvement of the caudate nucleus and the dentate nucleus were observed in the reported patients. MRS studies by both STEAM and PRESS spectra of all patients revealed a decrease in N-acetylaspartate and elevation in both myoinositol and choline. A pathologic peak at 1.33 ppm, which is compatible with lactate, and a particular peak at 2.42 ppm in all patients were also found. The combination of both MRI and MRS findings could be considered as being specific in patients with HMG-CoA lyase deficiency. © 1999 by Elsevier Science Inc. All rights reserved. Yalc¸ınkaya C, Dinc¸er A, Gu¨ndu¨z E, Fıc¸ıcıog˘lu C, Koc¸er N, Aydın A. MRI and MRS in HMG-CoA lyase deficiency. Pediatr Neurol 1999;20:375-380.
metabolic acidosis, and nonketotic hypoglycemia. Most children have hyperammonemia, elevated serum transamines, and hepatomegaly. About 30% of patients with this autosomal-recessive disorder become symptomatic in the neonatal period and about 60% between 3 and 12 months in the early infantile period. In the neonatal period the disease is fatal unless promptly treated [1]. Four organic acids are markedly elevated in urine; 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric, and 3-hydroxyisovaleric. The presence of these acids is considered to be characteristic of deficiency of HMG-CoA lyase, which is possible to assay on cultured fibroblasts and leukocytes [2]. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) studies were performed on a limited number of patients with HMG-CoA lyase deficiency; they presented with unique white matter involvement on MRI and nonspecific findings, such as decreased N-acetylaspartate (NAA)/Creatinine (Cr) and increased choline (Cho)/Cr and myoinositol (mI)/Cr, on MRS [3,4, 5,6,7]. In this report the authors discuss the specificity and diagnostic value of combined MRI and MRS findings supported especially by a particular peak at 2.42 ppm in single voxel proton spectroscopy of three patients with HMG-CoA lyase deficiency. Materials and Methods
Introduction 3-hydroxy-3-methylglutaryl coenzyme A lyase (HMGCoA) is an enzyme located in the mitochondrial matrix that catalyzes the final step in leucine degradation, converting HMG-CoA to acetyl-CoA and acetoacetic acid. The clinical presentation caused by HMG-CoA lyase deficiency is characterized by recurrent episodes of vomiting, hypotonia, tachypnea, seizures, lethargy or coma,
From the *Department of Neurology; Division of Child Neurology; Istanbul University; Cerrahpas¸a Medical Faculty; †Radyomar MRI Centre; ‡Department of Paediatrics, Division of Metabolic Diseases; and §Department of Radiology; Division of Neuroradiology; Istanbul University; Cerrahpas¸a Medical Faculty; Istanbul, Turkey.
© 1999 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00013-2 ● 0887-8994/99/$20.00
Three children (one male and two females, from 14 months to 7 years of age) with HMG-CoA lyase deficiency were evaluated. Onset of clinical features was in the early infantile period in two patients and in the neonatal period in the remaining one. Clinical features of the patients are listed in Table 1. Urinary organic acids and activity of HMG-CoA lyase in leukocytes were measured in all patients. Enzymatic analyses were performed by Dr. R. Wanders at the University of Amsterdam, Department of Genetic Metabolic Diseases. MRI and MRS were obtained for all patients. MRI scans were performed utilizing different clinical scanners, such as the 0.5 T MR Max (GE, Milwaukee, WI), the 1.0 T Magnetom Impact (Siemens, Erlangen,
Communications should be addressed to: Dr. Yalc¸ınkaya; Cumhuriyetci sok. No. 21; Kanat Apartment D: 17; TR-34740; Bakirko¨y-Istanbul, Turkey. Received September 2, 1998; accepted January 13, 1999.
Yalc¸inkaya et al: HMG-CoA Lyase Deficiency 375
Table 1. Patient No.
Clinical findings in patients with HMG-CoA lyase deficiency
Sex
Age
Age at Onset
Clinical Status at Onset
Follow-up
Biochemical Findings During Attacks
1
M
7 yr
14 mo
Seizure, vomiting, stupor, hepatomegaly
Seldom partial seizures, hyperactivity, mild mental retardation
2
F
15 mo
4 days
Seizure, vomiting, stupor, hepatomegaly
Three attacks until now right hemiparesis after last attack
3
F
14 mo
6 mo
Stupor, vomiting, hepatomegaly
Four attacks between 6-9 mo, current neurologic status normal
Germany), and the 1.5 T Signa (GE, Milwaukee, WI), using a protocol that included spin-echo T1-weighted images and spin-echo of fast spin-echo T2-weighted images in two different orthogonal planes at the minimum. All single voxel proton spectroscopy studies were obtained by a 1.5 T clinical scanner using PROBE/SV software (GE, Milwaukee, WI) that permitted automated shimming, water suppression, and data processing. T2-weighted axial images were used to locate the voxel in the parietooccipital white matter properly. Average voxel size was approximately 8 cm3. In two patients, both short and long TE spectra were obtained using point resolved spectroscopy (PRESS) (TR 5 1,500 ms, TE 5 270 ms, 128 acquisitions) and stimulated echo acquisition mode (TR 5 2,000 ms, TE 5 30 ms, 192 acquisitions). In Patient 2 a PRESS pulse sequence could only be performed. Both PRESS and stimulated echo acquisition mode pulse sequences were performed on the same patients in the same locations with equal voxel size. After immediate automatic processing of the raw data, spectra was evaluated qualitatively. Spectra were then quantified by peak height measurements. Ratios of metabolites relative to Cr were calculated and compared with values obtained from the control group consisting of two patients within the same age range.
Results Organic acid analyses in urine samples revealed markedly elevated 3-hydroxy-3-methylglutaric acid, 3-hydroxy glutaconic acid, 3-hydroxyglutaric acid, and 3-hydroxyTable 2.
isovaleric acid in all patients. HMG-CoA lyase enzyme activity in leukocytes was 0 nmol/minute/mg protein in two patients (Patients 1 and 3) and 0.03 nmol/minute/mg protein in Patient 2 (control 5 17.4 nmol/minute/mg protein). MRI findings of the patients are listed in Table 2. The common findings on all MRI scans are slightly increased diffuse T2-weighted signal intensity and a less prominent signal on T1-weighted images, which were distributed throughout the periventricular region and extended into the subcortical arcuate fibers and lobar white matter, most prominently in the parieto-occipital areas. In addition, multiple, well-demarcated, coalescent lesions of variable size superimposed on diffuse signal abnormality of white matter are seen on both T1-weighted and T2-weighted sequences. Partial involvement of subcortical arcuate fibers is present in all patients. Bilateral punctate lesions in the caudate nuclei are evident in all patients. Mild frontal atrophy and ventricular enlargement were seen in all patients. The corticopyramidal tract and the brainstem were unaffected. In Patient 1, involvement of caudate nuclei appeared initially on the right side and then involved both sides. Signal abnormalities in the dentate nuclei are demon-
MRI findings in patients with HMG-CoA deficiency
Arcuate fibers Lober white matter Periventricular white matter Corpus callosum Internal capsule External capsule 1 extreme Caudate nucleus Putamen Globus pallidus Thalamus Cerebellar pedunculi Nucleus dentatus Mesencephalon Pons Ventricular enlargement (mild) Cerebral atrophy (mild)
376
Hypoglycemia without ketosis, hyperammonemia, 1 transaminase Hypoglycemia without ketosis, hyperammonemia, 1 transaminase, 1 lactate Hypoglycemia without ketosis, 1 transaminase
PEDIATRIC NEUROLOGY
First MRI (15 mo)
Patient 1 Second MRI (4 yr)
Third MRI (7 yr)
First MRI (12 mo)
Patient 2 Second MRI (15 mo, during attack)
Patient 3 MRI (12 mo)
1 1 1 2 2 2 1/2 2 2 2 2 2 2 2 2 1
1 1 1 1 2 2 1/1 2 2 2 2 1/1 2 2 2 1
1 1 1 1 2 2 1/1 2 2 2 2 1/1 2 2 1 1
1 1 1 2 2 2 1/1 2 2 2 2 1/1 2 2 1 1
Swelling in the left hemisphere Swelling in the left hemisphere Swelling in the left hemisphere 2 2 2 1/1 2 1/1 2 2 1/1 2 2 2 right
1 1 1 2 2 2 1/1 2 2 2 2 2 2 2 1 1
Vol. 20 No. 5
Figure 1. Bilateral caudate nuclei and corpus callosum involvement on T2-weighted coronal image (TE 5 102; TR 5 4,800) in Patient 1.
strated in two patients. Involvement of the dentate nuclei was detectable 2 years after the first attack in Patient 1 and at the onset of symptoms in Patient 2. In Patient 1 the corpus callosum demonstrates signal abnormalities, and mild cerebellar atrophy is evident on the second MRI scan at 4 years of age (Figs 1,2). Patient 2 had the last metabolic attack at 15 months of age that caused left cerebral hemispheral swelling, compression of lateral ventricle, and hyperintensities in bilateral globus pallidi (Fig 3). Both PRESS and STEAM spectra in all patients revealed a decrease in NAA and elevation in both mI and
Figure 2. Multiple coalescent lesions in variable sizes superimposed on diffuse mild signal abnormality, bilateral dentate nuclei involvement, and mild cerebellar atrophy on T2-weighted coronal image (TE 5 90; TR 5 4,000) in Patient 1.
Figure 3. Left hemispheral swelling, diffuse hyperintensity in both white matter and cortex, loss of white and gray matter differentiation on spin echo T2-weighted axial image (TE 5 90; TR 5 2,200) in Patient 2.
Cho. There was a pathologic peak at 1.33 ppm in all spectra, which is compatible with lactate. Also, there was a particular peak at 2.42 ppm in all long and short TE spectra (Figs 4,5). Quantitative results are presented in Table 3. Discussion HMG-CoA lyase deficiency is a rare organic acidemia, but it is more frequently encountered in countries where consanguineous marriages often occur. The disease was first described by Faull et al. [8] and Wysocki et al. [9] in 1976. Clinical features are similar to those of Reye’s
Figure 4. Long TE spectra of Patient 1 demonstrate decreased NAA, increased Cho, and a particular peak at 2.42 ppm.
Yalc¸inkaya et al: HMG-CoA Lyase Deficiency 377
Figure 5. Short TE spectra of Patient 1 demonstrate decreased NAA, increased Cho, and a particular peak at 2.42 ppm.
syndrome, including vomiting, seizures, encephalopathy, and hepatic dysfunction. Attacks are triggered by infections or fasting and characterized by metabolic acidosis, hypoglycemia, without ketosis, elevated serum transaminases, and hyperammonemia. HMG-CoA lyase assessment in cultured fibroblasts and lymphocytes establishes the definitive diagnosis. The treatment consist of a lifelong low-protein diet and carnitine therapy. In nine patients, computed tomography (CT) scans were performed during metabolic attack, and diffuse hypodensity and white matter swelling were observed in all [3,5,10,11]. Asymmetric hemispheral swelling was demonstrated during an acute attack in one patient, and his brain biopsy revealed reactive gliosis, spongiosis, and increased intracellular astrocytic glycogen concentration in white matter [10]. In four patients from Saudi Arabia, prominent interhemispheric fissure and frontal sulci, slightly enlarged ventricles, and questionable white matter changes were suggested by CT scans that were performed between 10 days and 18 months after the metabolic attack [5]. Another report in which examinations were done 9-15 years after the attack in a sibling [3] (Table 4), mentioned patchy areas of decreased white matter density involving deep arcuate fibers in particular, which resulted in accentuation of gray-white matter differentiation in frontal and occipital areas. In the literature, MRI findings were reported in only 10 patients with HMG-CoA lyase deficiency. All studies were performed during a metabolically stabilized period. The only finding that was common to these reports was multiple, coalescent lesions in periventricular white matter and arcuate fibers, most prominently in frontal and periatrial regions on both T1-weighted and T2-weighted images. In some patients, multiple focal hyperintense lesions were superimposed on diffuse, slightly hyperintense sub-
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Vol. 20 No. 5
cortical white matter on T2-weighted images, whereas changes in signal intensity were less marked on T1weighted images. The combination of diffuse mild and multifocal more clearly delineated lesions on MRI images were considered unique [6]. Intensity changes in the head of the caudate nuclei, posterior limb of caudate nuclei, dentate nuclei, putamen, globi and pallidi, pontine tegmentum, and dorsolateral nuclei of thalami were also demonstrated [6,12] (Table 4). Serial MRI studies were performed in Patient 1; involvement of the caudate nucleus, dentate nucleus, and corpus callosum was evident in the course of the disease. Multiple focal lesions were pronounced on a background of diffuse, slightly increased signal from the subcortical white matter and centrum semiovale. U fibers involvement that suggested a previous arrest in myelination was evident at 7 years of age. Cerebellar cortical atrophy and corpus callosum involvement were also observed. We find these observations particularly interesting given the lack of similar findings in previous reports. Two MRI studies were performed in Patient 2, with the last one during an attack that manifested as right-sided focal seizures, right-sided hemiparesis, and severe hypoglycemia. This MRI examination demonstrated swelling of the left cerebral hemisphere and signal abnormalities in globi pallidi. To the authors’ knowledge, this is the first MRI examination performed during an attack. The findings were similar to those of CT during the acute attacks described earlier and considered to be caused by severe hypoglycemia resulting in occipital and basal ganglionic lesions [10]. However, it is also known that the severity of MRI changes does not correlate with the clinical status, and a certain degree of diffuse white matter abnormality can be present in neurologically normal or mildly mentally retarded patients. It is mostly accepted that basal ganglia and occipital lesions cause severe neurologic deficits. The actual discordance between clinical and imaging findings, such as those previously mentioned white matter abnormalities, is caused by hypomyelination and gliosis rather than progressive demyelination [6]. Serial MRI revealed limited progression of demyelination despite relatively Table 3.
Quantitative results of single voxel 1H spectroscopy
PRESS, 270 Spectra Patient No. NAA/Cr Cho/Cr 1 2 3 Control 1 Control 2
1.76 1.88 1.82 2.3 2.38
Abbreviations: Cho 5 Choline Cr 5 Creatine Lac 5 Lactate mI 5 Myo-inositole
1.47 1.98 1.91 1.36 1.38
STEAM, 30 Spectra Particular Lac/Cr peak/Cr mI/Cr 0.66 0.65 0.42 2 2
0.73 0.68 0.4 2 2
0.68 2 0.62 0.6 0.61
NAA 5 N-acetylaspartate PRESS 5 Point resolved spectroscopy STEAM 5 Stimulated echo acquisition mode
Table 4.
Summary of neuroradiologic data in the literature
Authors/Date of Publication
Patient No.
Lisson et al., 1981
1
Zoghbi et al., 1986 Ozand et al., 1991
Age of Onset
Clinical Status During Radiologic Investigation
2 mo
8 mo; macrocephaly, opisthotonus
1
6 mo, 2 wk
1
3 days
3 yr; severe motor and mental retardation 6 mo, 2 wk; somnolence, vomiting, seizure, hemiparesis 2 wk; normal
2
3
3 days
Swelling of left hemisphere, asymmetric lateral ventricule Prominent interhemispheric fissure, possible white matter abnormality 2 Quite marked interhemispheric fissure Questionable white matter disease bilaterally in centrum semiovale 2
4
2 mo
Dodelson et al., 1992
1
4 mo
Ferris 1992
1
Unknown
25 mo; normal
Yalc¸inkaya et al: HMG-CoA Lyase Deficiency 379
Van der Knaap et al., 1998
1 5 mo (Brother) 2 4 mo (Sister) 1 After birth
MRI
Course
2
Diffuse white matter hypodensity, bifrontal accentuation plus cystic areas, ventricular dilatation
Slightly enlarged ventricles, prominent frontal sulci 21 mo; mild developmental delay White matter changes in frontal and occipital regions, scattered minor lesions in subcortical white matter 10 mo; continuous myoclonic jerks, Marked widening of ventricles and sulci loss of vision, hepatomegaly and fissures 20 mo; severe neurologic sequelae
Gordon et al., 1994
6 mo
2 yr, 6 mo; no sequel after 5 acidotic attacks 1 mo, 2 wk; spastic quadriparesis, hepatomegaly 22 mo; attacks sometimes, no sequelae 32 mo.; normal
CT
2
3 yr; severe motor and mental retardation Died at 18 mo
2 2
Scattered lesions in subcortical white matter, changes 3 yr; normal around the frontal horn development 2
White matter lesions adjacent to the right horn
frontal
3 yr; normal
5 mo; normal
16 yr; seizure disorder 9 yr, 6 mo; seizure disorder 6 yr; normal neurodevelopment
2
Asymptomatic 10 yr; normal development
3
2 days
6 days; convulsion during metabolic acidosis
Patchy hypodensity in white matter preferentially involved deep arcuate fibers, fronto-ocipital accentuation Similar findings
Fronto-occipital white matter lesions with scattered changes throughout subcortical white matter 2
21 mo; mild delay Died at 19 mo
Right frontal and postparietal T2 hyperintensity, Severely retarded punctiform lesions in both caudate nuclei, cerebral atrophy Multiple confluent hyperintense lesions on T2Normal weighted with diffuse slight T2 hyperintensity in frontal and periatrial subcortical white matter, slightly enlarged sulci and ventricles Multifocal coalescent lesions predominantly in deep IQ 5 89 arcuate fibers Similar findings
Diffuse cerebral white matter hyperintensity sparing U fibers, less prominent T1-weighted and widespread marked small foci on both T1- and T2-weighted. Signal abnormalities in posterior limb of internal capsule and dentate nuclei Multiple foci with prominent signal abnormalities superimposed on diffuse cerebral white matter signal abnormality. U fibers affected. Involvement of posterior limb of internal capsule and dentate nuclei Diffuse hypodensity with swelling. 2 Diffuse abnormal signal intensity of atrophic parietomonths later, cystic degeneration seen occipital cortex and white matter. Signal in parieto-occipital white matter abnormalities in globus pallidum, pontine tegmentum, dentate nuclei, dorsolateral thalamus, putamen, and nucleus caudatus
IQ 5 91 6 yr; normal
10 yr; normal
4 yr; microcephalic, severely retarded
stable clinical status. The histopathologic and pathogenic aspects of these lesions remain to be clarified. Each one of the three patients demonstrates a moderate decrease in NAA/Cr and an increase in Cho/Cr. Both of these nonspecific findings in patients with HMG-CoA lyase deficiency have been reported by Van der Knaap et al. [6]. However, the increase in mI/Cr, which has been reported as another nonspecific finding by the same author, could be found only in one of three patients. The fact that this patient (Patient 1) is 7 years of age prompted us to interpret this increase in mI/Cr as being representative of the gliosis in the late stages of the disease process. In the 14-month-old patient (Patient 3), no increase in mI/Cr, which indicates glial proliferation, could be demonstrated. None of the three patients in the article by Van der Knaap et al. were as young as the authors’ patients, and, therefore, they most probably were in a later stage than the authors’ patients. The particular decrease of NAA, a marker of neuronal loss, which was more apparent in Patient 1, could be conceived as progression of the neuronal loss despite proper therapy. Cho increase, an indicator of the membrane turnover, was more evident in Patients 2 and 3 who were 15 and 14 months of age, respectively. Thus this finding could be construed as a proof of the conspicuity of disease activity in younger patients and earlier phase of the disease process. The double peak at 1.33 ppm in long TE spectra considered as being indicative of lactate was evident in all three patients. The lactate peak is hardly visible in a normal brain, and lactate is expected to rise in conditions where energy demand is increased; therefore, the lactate peak has been detected in tumors, ischemia, infarcts, and some metabolic diseases [13]. Another pathologic peak was detected at 2.42 ppm in both long and short TE spectra. In normal patients, good quality short TE spectra routinely demonstrate glutamineglutamate peak at 2.1-2.5 ppm. Glutamine and glutamate cannot be separated from each other using in vivo techniques. Normally, this peak cannot be seen in long TE spectra. In 1986, Iles et al. [7] reported 1H spectroscopic findings in the urine sample of patients with HMG-CoA lyase deficiency using in vitro technique. Contrary to the normal urine samples that demonstrate largest signals at creatinine (3.04-3.09 ppm) or, in very young children, creatine (3.05 ppm), in patients with HMG-CoA lyase deficiency, 1-D spectra reveal two large singlets at 1.28 and 1.33 ppm, another pair at 1.88 and 1.96 ppm, a singlet at 2.38 ppm, and a quartet at 2.47-2.55 ppm. In addition to these findings, some other peaks have also been identified. On the basis of spectra of standard solutions, they could assign the peaks at 1.28 and 2.38 ppm to 3-hydroxyisovalerate. In a similar way the peak at 1.33 ppm together with the quartet at 2.47-2.55 ppm could be assigned to 3-hydroxy-3-methylglutarate. By comparison of urine spectra from both healthy individuals and patients with other metabolic disorders, these findings have been thought as being diagnostic for HMG-CoA lyase deficiency [7].
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With respect to the findings described previously, and also considering that the spectral resolution of in vivo technique is less definite than that of in vitro, the particular peak we observed at 2.42 ppm in both short and long TE in vivo spectra could be assigned to increased levels of 3-hydroxyisovalerate and/or 3-hydroxy-3-methylglutarate. In addition to this the peak detected at 1.33 ppm and considered to be representative of lactate in all three patients could have been adjoined by 3-hydroxy-3-methylglutarate peak, which is demonstrated to be at the same location as lactate. To the authors’ knowledge a pathologic peak at 2.42 ppm in long TE spectra has not been described yet in other metabolic diseases. Along with this peak in long TE spectra, the peak at 1.33 ppm, representing either lactate or lactate and 3-hydoxy-3-methylglutarate that cannot be separated from each other, loss of NAA, increase in Cho, and increase in mI in later stages of the disease could be evaluated as being diagnostic for HMG-CoA lyase deficiency if accompanied by previously described MRI findings. References [1] Lyon G, Adams RD, Kolodny EH. The neurology of neonatal hereditary metabolic diseases. In: Lyon G, Adams RD, Kolodny EH, eds. Neurology of hereditary metabolic disease of children, 2nd ed. McGraw Hill, 1996:29-30. [2] Gibson KM, Breuer J, Kaiser K, et al. 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Report of five new patients. J Inher Metab Dis 1988;1:76-87. [3] Gordon K, Riding M, Camfield P, Bawden H, Ludman M, Bagnell P. CT and MR of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Am J Neuroradiol 1994;15:1474-6. [4] Ferris NJ, Tien RD. Cerebral MRI in 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Case report. Neuroradiology 1993; 35:559-60. [5] Ozand PT, Aqeel AA, Gascon G, Brismar J, Thomas E, Gleispach H. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency in Saudi Arabia. J Inher Metab Dis 1991;14:174-88. [6] Van der Knaap MS, Bakker HD, Valk J. MR Imaging and proton spectroscopy in 3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency. Am J Neuroradiol 1998;19:378-82. [7] Iles R, Jago JR, Williams SR, Chalmers RA. 3-hydroxy-3methylglutaryl-coenzyme A lyase deficiency studied using 2-dimensional proton nuclear magnetic resonance spectroscopy. FEBS Lett 1986;203:49-53. [8] Faull FK, Bolton P, Halpern B, et al. Patient with defect in leucine metabolism (Letter). N Engl J Med 1976;294:1013. [9] Wysocki SJ, Wilkonson SP, Haehnel R, Wong CYB, Panegyres PK. 3-hydroxy-3-methylglutaric aciduria, combined with 3-methylglutaconic aciduria. Clin Chim Acta 1976;70:399-406. [10] Zoghbi H, Spence E, Beaudet A, O’Brien WE, Goodman CJ, Gibson KM. Atypical presentation and neuropathological studies in 3-hydroxy-3-Methylglutaryl coenzyme A lyase deficiency. Ann Neurol 1986;20:367-9. [11] Lisson G, Leopold D, Bechinger D, Wallech C. CT findings in a case of deficiency of 3-hydroxy-3-methylglutaryl-coenzyme-A-lyase. Neuroradiology 1981;22:99-101. [12] Dodelson de Kremer R, Kelley RI, Depetris de BC, et al. 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency as a cause of severe neurological damage. Medicina (B Aires) 1992;52:30-6 (abstract). [13] Castillo M, Kwock L, Mukherji SK. Clinical applications of proton MR Spectroscopy. Am J Neuroradiol 1996;17:1-15.
metabolic acidosis, and nonketotic hypoglycemia. Most children have hyperammonemia, elevated serum transamines, and hepatomegaly. About 30% of patients with this autosomal-recessive disorder become symptomatic in the neonatal period and about 60% between 3 and 12 months in the early infantile period. In the neonatal period the disease is fatal unless promptly treated [1]. Four organic acids are markedly elevated in urine; 3-hydroxy-3-methylglutaric, 3-methylglutaconic, 3-methylglutaric, and 3-hydroxyisovaleric. The presence of these acids is considered to be characteristic of deficiency of HMG-CoA lyase, which is possible to assay on cultured fibroblasts and leukocytes [2]. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) studies were performed on a limited number of patients with HMG-CoA lyase deficiency; they presented with unique white matter involvement on MRI and nonspecific findings, such as decreased N-acetylaspartate (NAA)/Creatinine (Cr) and increased choline (Cho)/Cr and myoinositol (mI)/Cr, on MRS [3,4, 5,6,7]. In this report the authors discuss the specificity and diagnostic value of combined MRI and MRS findings supported especially by a particular peak at 2.42 ppm in single voxel proton spectroscopy of three patients with HMG-CoA lyase deficiency. Materials and Methods
Introduction 3-hydroxy-3-methylglutaryl coenzyme A lyase (HMGCoA) is an enzyme located in the mitochondrial matrix that catalyzes the final step in leucine degradation, converting HMG-CoA to acetyl-CoA and acetoacetic acid. The clinical presentation caused by HMG-CoA lyase deficiency is characterized by recurrent episodes of vomiting, hypotonia, tachypnea, seizures, lethargy or coma,
From the *Department of Neurology; Division of Child Neurology; Istanbul University; Cerrahpas¸a Medical Faculty; †Radyomar MRI Centre; ‡Department of Paediatrics, Division of Metabolic Diseases; and §Department of Radiology; Division of Neuroradiology; Istanbul University; Cerrahpas¸a Medical Faculty; Istanbul, Turkey.
© 1999 by Elsevier Science Inc. All rights reserved. PII S0887-8994(99)00013-2 ● 0887-8994/99/$20.00
Three children (one male and two females, from 14 months to 7 years of age) with HMG-CoA lyase deficiency were evaluated. Onset of clinical features was in the early infantile period in two patients and in the neonatal period in the remaining one. Clinical features of the patients are listed in Table 1. Urinary organic acids and activity of HMG-CoA lyase in leukocytes were measured in all patients. Enzymatic analyses were performed by Dr. R. Wanders at the University of Amsterdam, Department of Genetic Metabolic Diseases. MRI and MRS were obtained for all patients. MRI scans were performed utilizing different clinical scanners, such as the 0.5 T MR Max (GE, Milwaukee, WI), the 1.0 T Magnetom Impact (Siemens, Erlangen,
Communications should be addressed to: Dr. Yalc¸ınkaya; Cumhuriyetci sok. No. 21; Kanat Apartment D: 17; TR-34740; Bakirko¨y-Istanbul, Turkey. Received September 2, 1998; accepted January 13, 1999.
Yalc¸inkaya et al: HMG-CoA Lyase Deficiency 375
Table 1. Patient No.
Clinical findings in patients with HMG-CoA lyase deficiency
Sex
Age
Age at Onset
Clinical Status at Onset
Follow-up
Biochemical Findings During Attacks
1
M
7 yr
14 mo
Seizure, vomiting, stupor, hepatomegaly
Seldom partial seizures, hyperactivity, mild mental retardation
2
F
15 mo
4 days
Seizure, vomiting, stupor, hepatomegaly
Three attacks until now right hemiparesis after last attack
3
F
14 mo
6 mo
Stupor, vomiting, hepatomegaly
Four attacks between 6-9 mo, current neurologic status normal
Germany), and the 1.5 T Signa (GE, Milwaukee, WI), using a protocol that included spin-echo T1-weighted images and spin-echo of fast spin-echo T2-weighted images in two different orthogonal planes at the minimum. All single voxel proton spectroscopy studies were obtained by a 1.5 T clinical scanner using PROBE/SV software (GE, Milwaukee, WI) that permitted automated shimming, water suppression, and data processing. T2-weighted axial images were used to locate the voxel in the parietooccipital white matter properly. Average voxel size was approximately 8 cm3. In two patients, both short and long TE spectra were obtained using point resolved spectroscopy (PRESS) (TR 5 1,500 ms, TE 5 270 ms, 128 acquisitions) and stimulated echo acquisition mode (TR 5 2,000 ms, TE 5 30 ms, 192 acquisitions). In Patient 2 a PRESS pulse sequence could only be performed. Both PRESS and stimulated echo acquisition mode pulse sequences were performed on the same patients in the same locations with equal voxel size. After immediate automatic processing of the raw data, spectra was evaluated qualitatively. Spectra were then quantified by peak height measurements. Ratios of metabolites relative to Cr were calculated and compared with values obtained from the control group consisting of two patients within the same age range.
Results Organic acid analyses in urine samples revealed markedly elevated 3-hydroxy-3-methylglutaric acid, 3-hydroxy glutaconic acid, 3-hydroxyglutaric acid, and 3-hydroxyTable 2.
isovaleric acid in all patients. HMG-CoA lyase enzyme activity in leukocytes was 0 nmol/minute/mg protein in two patients (Patients 1 and 3) and 0.03 nmol/minute/mg protein in Patient 2 (control 5 17.4 nmol/minute/mg protein). MRI findings of the patients are listed in Table 2. The common findings on all MRI scans are slightly increased diffuse T2-weighted signal intensity and a less prominent signal on T1-weighted images, which were distributed throughout the periventricular region and extended into the subcortical arcuate fibers and lobar white matter, most prominently in the parieto-occipital areas. In addition, multiple, well-demarcated, coalescent lesions of variable size superimposed on diffuse signal abnormality of white matter are seen on both T1-weighted and T2-weighted sequences. Partial involvement of subcortical arcuate fibers is present in all patients. Bilateral punctate lesions in the caudate nuclei are evident in all patients. Mild frontal atrophy and ventricular enlargement were seen in all patients. The corticopyramidal tract and the brainstem were unaffected. In Patient 1, involvement of caudate nuclei appeared initially on the right side and then involved both sides. Signal abnormalities in the dentate nuclei are demon-
MRI findings in patients with HMG-CoA deficiency
Arcuate fibers Lober white matter Periventricular white matter Corpus callosum Internal capsule External capsule 1 extreme Caudate nucleus Putamen Globus pallidus Thalamus Cerebellar pedunculi Nucleus dentatus Mesencephalon Pons Ventricular enlargement (mild) Cerebral atrophy (mild)
376
Hypoglycemia without ketosis, hyperammonemia, 1 transaminase Hypoglycemia without ketosis, hyperammonemia, 1 transaminase, 1 lactate Hypoglycemia without ketosis, 1 transaminase
PEDIATRIC NEUROLOGY
First MRI (15 mo)
Patient 1 Second MRI (4 yr)
Third MRI (7 yr)
First MRI (12 mo)
Patient 2 Second MRI (15 mo, during attack)
Patient 3 MRI (12 mo)
1 1 1 2 2 2 1/2 2 2 2 2 2 2 2 2 1
1 1 1 1 2 2 1/1 2 2 2 2 1/1 2 2 2 1
1 1 1 1 2 2 1/1 2 2 2 2 1/1 2 2 1 1
1 1 1 2 2 2 1/1 2 2 2 2 1/1 2 2 1 1
Swelling in the left hemisphere Swelling in the left hemisphere Swelling in the left hemisphere 2 2 2 1/1 2 1/1 2 2 1/1 2 2 2 right
1 1 1 2 2 2 1/1 2 2 2 2 2 2 2 1 1
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Figure 1. Bilateral caudate nuclei and corpus callosum involvement on T2-weighted coronal image (TE 5 102; TR 5 4,800) in Patient 1.
strated in two patients. Involvement of the dentate nuclei was detectable 2 years after the first attack in Patient 1 and at the onset of symptoms in Patient 2. In Patient 1 the corpus callosum demonstrates signal abnormalities, and mild cerebellar atrophy is evident on the second MRI scan at 4 years of age (Figs 1,2). Patient 2 had the last metabolic attack at 15 months of age that caused left cerebral hemispheral swelling, compression of lateral ventricle, and hyperintensities in bilateral globus pallidi (Fig 3). Both PRESS and STEAM spectra in all patients revealed a decrease in NAA and elevation in both mI and
Figure 2. Multiple coalescent lesions in variable sizes superimposed on diffuse mild signal abnormality, bilateral dentate nuclei involvement, and mild cerebellar atrophy on T2-weighted coronal image (TE 5 90; TR 5 4,000) in Patient 1.
Figure 3. Left hemispheral swelling, diffuse hyperintensity in both white matter and cortex, loss of white and gray matter differentiation on spin echo T2-weighted axial image (TE 5 90; TR 5 2,200) in Patient 2.
Cho. There was a pathologic peak at 1.33 ppm in all spectra, which is compatible with lactate. Also, there was a particular peak at 2.42 ppm in all long and short TE spectra (Figs 4,5). Quantitative results are presented in Table 3. Discussion HMG-CoA lyase deficiency is a rare organic acidemia, but it is more frequently encountered in countries where consanguineous marriages often occur. The disease was first described by Faull et al. [8] and Wysocki et al. [9] in 1976. Clinical features are similar to those of Reye’s
Figure 4. Long TE spectra of Patient 1 demonstrate decreased NAA, increased Cho, and a particular peak at 2.42 ppm.
Yalc¸inkaya et al: HMG-CoA Lyase Deficiency 377
Figure 5. Short TE spectra of Patient 1 demonstrate decreased NAA, increased Cho, and a particular peak at 2.42 ppm.
syndrome, including vomiting, seizures, encephalopathy, and hepatic dysfunction. Attacks are triggered by infections or fasting and characterized by metabolic acidosis, hypoglycemia, without ketosis, elevated serum transaminases, and hyperammonemia. HMG-CoA lyase assessment in cultured fibroblasts and lymphocytes establishes the definitive diagnosis. The treatment consist of a lifelong low-protein diet and carnitine therapy. In nine patients, computed tomography (CT) scans were performed during metabolic attack, and diffuse hypodensity and white matter swelling were observed in all [3,5,10,11]. Asymmetric hemispheral swelling was demonstrated during an acute attack in one patient, and his brain biopsy revealed reactive gliosis, spongiosis, and increased intracellular astrocytic glycogen concentration in white matter [10]. In four patients from Saudi Arabia, prominent interhemispheric fissure and frontal sulci, slightly enlarged ventricles, and questionable white matter changes were suggested by CT scans that were performed between 10 days and 18 months after the metabolic attack [5]. Another report in which examinations were done 9-15 years after the attack in a sibling [3] (Table 4), mentioned patchy areas of decreased white matter density involving deep arcuate fibers in particular, which resulted in accentuation of gray-white matter differentiation in frontal and occipital areas. In the literature, MRI findings were reported in only 10 patients with HMG-CoA lyase deficiency. All studies were performed during a metabolically stabilized period. The only finding that was common to these reports was multiple, coalescent lesions in periventricular white matter and arcuate fibers, most prominently in frontal and periatrial regions on both T1-weighted and T2-weighted images. In some patients, multiple focal hyperintense lesions were superimposed on diffuse, slightly hyperintense sub-
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cortical white matter on T2-weighted images, whereas changes in signal intensity were less marked on T1weighted images. The combination of diffuse mild and multifocal more clearly delineated lesions on MRI images were considered unique [6]. Intensity changes in the head of the caudate nuclei, posterior limb of caudate nuclei, dentate nuclei, putamen, globi and pallidi, pontine tegmentum, and dorsolateral nuclei of thalami were also demonstrated [6,12] (Table 4). Serial MRI studies were performed in Patient 1; involvement of the caudate nucleus, dentate nucleus, and corpus callosum was evident in the course of the disease. Multiple focal lesions were pronounced on a background of diffuse, slightly increased signal from the subcortical white matter and centrum semiovale. U fibers involvement that suggested a previous arrest in myelination was evident at 7 years of age. Cerebellar cortical atrophy and corpus callosum involvement were also observed. We find these observations particularly interesting given the lack of similar findings in previous reports. Two MRI studies were performed in Patient 2, with the last one during an attack that manifested as right-sided focal seizures, right-sided hemiparesis, and severe hypoglycemia. This MRI examination demonstrated swelling of the left cerebral hemisphere and signal abnormalities in globi pallidi. To the authors’ knowledge, this is the first MRI examination performed during an attack. The findings were similar to those of CT during the acute attacks described earlier and considered to be caused by severe hypoglycemia resulting in occipital and basal ganglionic lesions [10]. However, it is also known that the severity of MRI changes does not correlate with the clinical status, and a certain degree of diffuse white matter abnormality can be present in neurologically normal or mildly mentally retarded patients. It is mostly accepted that basal ganglia and occipital lesions cause severe neurologic deficits. The actual discordance between clinical and imaging findings, such as those previously mentioned white matter abnormalities, is caused by hypomyelination and gliosis rather than progressive demyelination [6]. Serial MRI revealed limited progression of demyelination despite relatively Table 3.
Quantitative results of single voxel 1H spectroscopy
PRESS, 270 Spectra Patient No. NAA/Cr Cho/Cr 1 2 3 Control 1 Control 2
1.76 1.88 1.82 2.3 2.38
Abbreviations: Cho 5 Choline Cr 5 Creatine Lac 5 Lactate mI 5 Myo-inositole
1.47 1.98 1.91 1.36 1.38
STEAM, 30 Spectra Particular Lac/Cr peak/Cr mI/Cr 0.66 0.65 0.42 2 2
0.73 0.68 0.4 2 2
0.68 2 0.62 0.6 0.61
NAA 5 N-acetylaspartate PRESS 5 Point resolved spectroscopy STEAM 5 Stimulated echo acquisition mode
Table 4.
Summary of neuroradiologic data in the literature
Authors/Date of Publication
Patient No.
Lisson et al., 1981
1
Zoghbi et al., 1986 Ozand et al., 1991
Age of Onset
Clinical Status During Radiologic Investigation
2 mo
8 mo; macrocephaly, opisthotonus
1
6 mo, 2 wk
1
3 days
3 yr; severe motor and mental retardation 6 mo, 2 wk; somnolence, vomiting, seizure, hemiparesis 2 wk; normal
2
3
3 days
Swelling of left hemisphere, asymmetric lateral ventricule Prominent interhemispheric fissure, possible white matter abnormality 2 Quite marked interhemispheric fissure Questionable white matter disease bilaterally in centrum semiovale 2
4
2 mo
Dodelson et al., 1992
1
4 mo
Ferris 1992
1
Unknown
25 mo; normal
Yalc¸inkaya et al: HMG-CoA Lyase Deficiency 379
Van der Knaap et al., 1998
1 5 mo (Brother) 2 4 mo (Sister) 1 After birth
MRI
Course
2
Diffuse white matter hypodensity, bifrontal accentuation plus cystic areas, ventricular dilatation
Slightly enlarged ventricles, prominent frontal sulci 21 mo; mild developmental delay White matter changes in frontal and occipital regions, scattered minor lesions in subcortical white matter 10 mo; continuous myoclonic jerks, Marked widening of ventricles and sulci loss of vision, hepatomegaly and fissures 20 mo; severe neurologic sequelae
Gordon et al., 1994
6 mo
2 yr, 6 mo; no sequel after 5 acidotic attacks 1 mo, 2 wk; spastic quadriparesis, hepatomegaly 22 mo; attacks sometimes, no sequelae 32 mo.; normal
CT
2
3 yr; severe motor and mental retardation Died at 18 mo
2 2
Scattered lesions in subcortical white matter, changes 3 yr; normal around the frontal horn development 2
White matter lesions adjacent to the right horn
frontal
3 yr; normal
5 mo; normal
16 yr; seizure disorder 9 yr, 6 mo; seizure disorder 6 yr; normal neurodevelopment
2
Asymptomatic 10 yr; normal development
3
2 days
6 days; convulsion during metabolic acidosis
Patchy hypodensity in white matter preferentially involved deep arcuate fibers, fronto-ocipital accentuation Similar findings
Fronto-occipital white matter lesions with scattered changes throughout subcortical white matter 2
21 mo; mild delay Died at 19 mo
Right frontal and postparietal T2 hyperintensity, Severely retarded punctiform lesions in both caudate nuclei, cerebral atrophy Multiple confluent hyperintense lesions on T2Normal weighted with diffuse slight T2 hyperintensity in frontal and periatrial subcortical white matter, slightly enlarged sulci and ventricles Multifocal coalescent lesions predominantly in deep IQ 5 89 arcuate fibers Similar findings
Diffuse cerebral white matter hyperintensity sparing U fibers, less prominent T1-weighted and widespread marked small foci on both T1- and T2-weighted. Signal abnormalities in posterior limb of internal capsule and dentate nuclei Multiple foci with prominent signal abnormalities superimposed on diffuse cerebral white matter signal abnormality. U fibers affected. Involvement of posterior limb of internal capsule and dentate nuclei Diffuse hypodensity with swelling. 2 Diffuse abnormal signal intensity of atrophic parietomonths later, cystic degeneration seen occipital cortex and white matter. Signal in parieto-occipital white matter abnormalities in globus pallidum, pontine tegmentum, dentate nuclei, dorsolateral thalamus, putamen, and nucleus caudatus
IQ 5 91 6 yr; normal
10 yr; normal
4 yr; microcephalic, severely retarded
stable clinical status. The histopathologic and pathogenic aspects of these lesions remain to be clarified. Each one of the three patients demonstrates a moderate decrease in NAA/Cr and an increase in Cho/Cr. Both of these nonspecific findings in patients with HMG-CoA lyase deficiency have been reported by Van der Knaap et al. [6]. However, the increase in mI/Cr, which has been reported as another nonspecific finding by the same author, could be found only in one of three patients. The fact that this patient (Patient 1) is 7 years of age prompted us to interpret this increase in mI/Cr as being representative of the gliosis in the late stages of the disease process. In the 14-month-old patient (Patient 3), no increase in mI/Cr, which indicates glial proliferation, could be demonstrated. None of the three patients in the article by Van der Knaap et al. were as young as the authors’ patients, and, therefore, they most probably were in a later stage than the authors’ patients. The particular decrease of NAA, a marker of neuronal loss, which was more apparent in Patient 1, could be conceived as progression of the neuronal loss despite proper therapy. Cho increase, an indicator of the membrane turnover, was more evident in Patients 2 and 3 who were 15 and 14 months of age, respectively. Thus this finding could be construed as a proof of the conspicuity of disease activity in younger patients and earlier phase of the disease process. The double peak at 1.33 ppm in long TE spectra considered as being indicative of lactate was evident in all three patients. The lactate peak is hardly visible in a normal brain, and lactate is expected to rise in conditions where energy demand is increased; therefore, the lactate peak has been detected in tumors, ischemia, infarcts, and some metabolic diseases [13]. Another pathologic peak was detected at 2.42 ppm in both long and short TE spectra. In normal patients, good quality short TE spectra routinely demonstrate glutamineglutamate peak at 2.1-2.5 ppm. Glutamine and glutamate cannot be separated from each other using in vivo techniques. Normally, this peak cannot be seen in long TE spectra. In 1986, Iles et al. [7] reported 1H spectroscopic findings in the urine sample of patients with HMG-CoA lyase deficiency using in vitro technique. Contrary to the normal urine samples that demonstrate largest signals at creatinine (3.04-3.09 ppm) or, in very young children, creatine (3.05 ppm), in patients with HMG-CoA lyase deficiency, 1-D spectra reveal two large singlets at 1.28 and 1.33 ppm, another pair at 1.88 and 1.96 ppm, a singlet at 2.38 ppm, and a quartet at 2.47-2.55 ppm. In addition to these findings, some other peaks have also been identified. On the basis of spectra of standard solutions, they could assign the peaks at 1.28 and 2.38 ppm to 3-hydroxyisovalerate. In a similar way the peak at 1.33 ppm together with the quartet at 2.47-2.55 ppm could be assigned to 3-hydroxy-3-methylglutarate. By comparison of urine spectra from both healthy individuals and patients with other metabolic disorders, these findings have been thought as being diagnostic for HMG-CoA lyase deficiency [7].
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With respect to the findings described previously, and also considering that the spectral resolution of in vivo technique is less definite than that of in vitro, the particular peak we observed at 2.42 ppm in both short and long TE in vivo spectra could be assigned to increased levels of 3-hydroxyisovalerate and/or 3-hydroxy-3-methylglutarate. In addition to this the peak detected at 1.33 ppm and considered to be representative of lactate in all three patients could have been adjoined by 3-hydroxy-3-methylglutarate peak, which is demonstrated to be at the same location as lactate. To the authors’ knowledge a pathologic peak at 2.42 ppm in long TE spectra has not been described yet in other metabolic diseases. Along with this peak in long TE spectra, the peak at 1.33 ppm, representing either lactate or lactate and 3-hydoxy-3-methylglutarate that cannot be separated from each other, loss of NAA, increase in Cho, and increase in mI in later stages of the disease could be evaluated as being diagnostic for HMG-CoA lyase deficiency if accompanied by previously described MRI findings. References [1] Lyon G, Adams RD, Kolodny EH. The neurology of neonatal hereditary metabolic diseases. In: Lyon G, Adams RD, Kolodny EH, eds. Neurology of hereditary metabolic disease of children, 2nd ed. McGraw Hill, 1996:29-30. [2] Gibson KM, Breuer J, Kaiser K, et al. 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Report of five new patients. J Inher Metab Dis 1988;1:76-87. [3] Gordon K, Riding M, Camfield P, Bawden H, Ludman M, Bagnell P. CT and MR of 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Am J Neuroradiol 1994;15:1474-6. [4] Ferris NJ, Tien RD. Cerebral MRI in 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Case report. Neuroradiology 1993; 35:559-60. [5] Ozand PT, Aqeel AA, Gascon G, Brismar J, Thomas E, Gleispach H. 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) lyase deficiency in Saudi Arabia. J Inher Metab Dis 1991;14:174-88. [6] Van der Knaap MS, Bakker HD, Valk J. MR Imaging and proton spectroscopy in 3-hydroxy-3-methylglutaryl coenzyme A lyase deficiency. Am J Neuroradiol 1998;19:378-82. [7] Iles R, Jago JR, Williams SR, Chalmers RA. 3-hydroxy-3methylglutaryl-coenzyme A lyase deficiency studied using 2-dimensional proton nuclear magnetic resonance spectroscopy. FEBS Lett 1986;203:49-53. [8] Faull FK, Bolton P, Halpern B, et al. Patient with defect in leucine metabolism (Letter). N Engl J Med 1976;294:1013. [9] Wysocki SJ, Wilkonson SP, Haehnel R, Wong CYB, Panegyres PK. 3-hydroxy-3-methylglutaric aciduria, combined with 3-methylglutaconic aciduria. Clin Chim Acta 1976;70:399-406. [10] Zoghbi H, Spence E, Beaudet A, O’Brien WE, Goodman CJ, Gibson KM. Atypical presentation and neuropathological studies in 3-hydroxy-3-Methylglutaryl coenzyme A lyase deficiency. Ann Neurol 1986;20:367-9. [11] Lisson G, Leopold D, Bechinger D, Wallech C. CT findings in a case of deficiency of 3-hydroxy-3-methylglutaryl-coenzyme-A-lyase. Neuroradiology 1981;22:99-101. [12] Dodelson de Kremer R, Kelley RI, Depetris de BC, et al. 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency as a cause of severe neurological damage. Medicina (B Aires) 1992;52:30-6 (abstract). [13] Castillo M, Kwock L, Mukherji SK. Clinical applications of proton MR Spectroscopy. Am J Neuroradiol 1996;17:1-15.