James E Knake

Joseph T Latack

Stephen S Gebarski &apos

Trygve O Gabrielsen

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Stephen S. Gebarski ' 
Trygve O. Gabrielsen 
James E. Knake 
Joseph T. Latack 
Received October 5, 1982; accepted after re-
vision December 17, 1982. 
, All authors: Division of Neuroradiology, De-
partment of Radiology, Box 13, University of Mich-
igan Hospitals, Ann Arbor, MI 48109. A'ddress 
reprint requests to S. S. Gebarski. 
AJNR 4:955-957, July/August 1983 
0 195- 6108 / 83 / 0404-0955 $00.00 
© American Roentgen Ray Society 
Cerebral CT Findings in 
Methylmalonic and 
Propionic Acidemias 
955 
The cerebral computed tomographic findings in two infants with methylmalonic 
acidemia and one infant and one adult with propionic acidemia are presented. Pertinent 
metabolic, clinical, and pathologic features of these genetic disorders of vitamin B'2 
(cobalamin) and biotin metabolism are reviewed briefly. Computed tomographic abnor-
malities consist of focal or diffuse deep cerebral hemisphere lucencies and diffuse loss 
of brain substance. These findings correlated well with the clinical and pathologic 
findings. The leukoencephalopathy in these uncommon autosomal recessive conditions 
appears to be due to ketoacidosis, which in some cases may be managed by vitamin 
supplementation. 
Methylmalonic acidemia (MMA) and propionic acidemia (PA) are genetic dis-
orders of amino acid metabolism. They both involve defective conversion of 
propionate to succinate, with c linical presentations early in life dominated by 
ketoacidosis without diabetes mellitus, sepsis , or other common cause [1-10]. 
The neurologic abnormalities in most patients can be attributed to the ketoaci-
dosis. The final , specific diagnosis is biochemical, and early detection with proper 
therapy may permit normal neurologic development [2, 9]. Previous reports on 
MMA and PA have helped to increase the cl inical awareness of these conditions 
[1-10]. Although a case of PA has been included in a general computed 
tomographic (CT) review of white-matter diseases [11], more specific and com-
prehensive reports on the cerebral CT findings in MMA and PA are lack ing and 
prompted the present report. 
Materials and Method 
During a 5 year period , two patients with the c linical d iagnosis of MMA and two patients 
with the clinical diagnosis of PA underwent CT. All studies were performed on an updated 
EMI 1005 scanner using a 60 sec scan time, 160 x 160 matrix, and 8 mm collimator. 
Case Reports 
Case 1 
A 1-month-old boy had severe ketoacidosis and hyperglycinemia. Elevated levels of 
methylmalonic acid were found in urine and serum. No megaloblastic anemia was seen . 
Serum B' 2 was normal. CT showed diffuse leukoencephalopathy (fig . 1). The patient had 
a stormy c linical course with development of ci rrhosis, ascites, and malnutrition . No 
response to vitamin B' 2 was noted . Death occurred at 4 years of age due to c irrhosis. 
Autopsy showed diffuse cerebral and cerebellar atrophy, most marked in the white matter. 
Case 2 
A 4-month-old girl had delayed development and spastic quadriparesis . Urine and serum 
956 GEBARSKI ET AL. AJNR:4, Jul./ Aug. 1983 
B 
Fig. 1.- Case 1. CT at 1 month of age shows diffuse leukoencephalopath y. 
analysis revealed elevated levels of methylmalonic acid, which were 
found to be responsive to vitamin 8 ' 2 treatment. Pretreatment serum 
8 ' 2 levels were normal. Th ere was no evidence of homocystinuria. 
CT at 12 months of age showed diffuse loss of cerebral substance 
and focal white-matter lucenc ies in the posterior limbs of the intern al 
capsules (fig. 2). Follow-up scan 3 months later showed no signifi-
cant change. The patient has been receiving outpatient care for 
severe mental retardation and spastic quadriparesis. 
Case 3 
A 2-month-old girl had ketoac idosis, hypergl yc inemia, and spas-
tic quadriparesis. Elevated propionic ac id levels were found in urine 
and serum . CT at 3'12 years of age showed diffuse cerebral atrophy 
(fig. 3). No c linica l response to biotin or protein restriction was 
noted. Outpatient follow-up showed a stable c linica l statu s. No 
fu rth er CT was done. 
Case 4 
A 17-year-old woman presented with mild mental retardation and 
headache. Elevated propionic acid levels were found in urine and 
serum . CT after intravenous infusion of 100 ml Conray-60 (meglu-
mine ioth alamate 60%) suggested a subtle lucency in the posterior 
limb of the right intern al capsule (fig . 4) . There was no pathologic 
contrast enhancement. No history to suggest transient ischemic 
attack or stroke was elic ited . Outpatient follow-up inc luded biotin 
therapy and protein restriction, without c linica l change. No further 
CT was performed. 
Discussion 
Acquired vitamin deficiency can be produced by nutri-
tional , absorptive, pharmacologic , or developmental inter-
ferences with vitamin utilization . In contrast, some individu-
als have a constant, specific requirement for a particular 
vitamin that differs from normal , either in requiring parenteral 
rather than oral vitamin administration or in requiring 10 to 
10,000 times the quantity of vitamin that is recommended 
normally. The vitamin-dependent or vitamin-responsive con-
ditions in such pati ents result from a genetically determined 
A 
Fig. 2. - Case 2. CT at 1 year of age demonstrates decreased attenuati on 
in posteri or limbs of intern al capsules (A, arro ws ), moderate diffuse loss of 
cerebral substance , and decreased attenuation in white matter of left frontal 
lobe (8) . 
biochemical abnormality , which usually involves only a sin-
gle reaction [10]. 
Of the inherited disorders of vitamin B' 2 metabolism, at 
least eight different human mutations have been identified , 
three of intestinal absorption , two of plasma transport, and 
three of ti ssue utilization. The last category constitutes the 
MMAs [10]. 
MMA usually presents in childhood with unexplained ke-
toacidosis and elevated levels of methyl malonic acid in 
blood and urine [4]. The biochemical deficit lies in deranged 
methyl malonic acid coenzyme A metabolism [5]. Two gen-
eral subtypes exist, both with autosomal recessive inheri-
tance patterns. The first subtype presents with a classic 
pattern of ketoacidosis, hyperglycinemia, and mental retar-
dation . Both cobalamin (vitamin Bd-responsive and cobal-
amin-unresponsive forms of this subtype have been found 
[10]. Clinical management includes protein restriction and 
cobalamin supplementation . Simple cobalamin deficiency in 
infants and children is rare but must be ruled out early in 
the diagnostic workup [9]. The second subtype is associated 
with deranged sulfur amino acid metabolism, mental retar-
dation, and no ketoacidosis . This subjype is better consid-
ered with homocystinuria [8] and is not discussed further in 
this report. 
Biotin serves as a coenzyme in a number of ATP-depen-
dent carboxylations . If there is a primary defect in the activity 
of the biotin-dependent enzyme propionyl-CoA carboxylase, 
the affected infants and children accumulate large amounts 
of proprionate in the blood (PA) and urine (propionic aci-
duria) [10]. The biochemical deficit appears to be inherited 
in an autosomal recessive pattern [7]. The clinical course of 
these patients has often been devastating , with neonatal 
ketosis, acidosis , failure to thrive , protein intolerance, and 
early demise. Both biotin-responsive and biotin-unrespon-
sive forms have been reported [10]. Therapy includes pro-
tein restriction and careful treatment of secondary infections 
[2 , 9]. 
MMA and PA have been associated with the older term 
AJNR:4, Jul. / Aug. 1983 METHYLMALONIC AND PROPIONIC ACIDEMIAS 957 
Fig . 3. - Case 3. CT at 3'/2 years of 
age shows moderate to severe diffuse 
ce rebral atrophy . 
Fig . 4. - Case 4 . Contrast-enhanced 
CT at 17 years of age suggests subtle 
area of decreased attenuation in poste-
rior limb of right internal capsule (arrow). 
3A 
" ketotic hyperglycinemia," which is confusing and probably 
should be discarded not on ly because hyperglycinemia is 
not a specific or constant finding in MMA and PA, but it also 
erroneously suggests a primary abnormality of glycine me-
tabolism in these conditions [6, 9]. 
For neuroradiologic purposes, MMA and PA can be con-
sidered together. These patients may be seen early in the 
clinical workup of unexplained ketoacidosis or after a spe-
cific biochemical diagnosis has been made. In our patients, 
the cerebral hemispheric white matter is affected most se-
verely. Not surprisingly , mild CT abnormalities are associ-
ated with mild clinical impairment (case 4) . The most pro-
foundly affected patients (cases 1 -3) demonstrate severe 
leukoencephalopathy and diffuse loss of cerebral sub-
stance . All our patients were examined on a 60 sec scanner, 
and it is conceivable that they may appear somewhat differ-
ent on a newer type scanner. While none of our patients 
had a chronologically complete series of CT scans, one 
case of PA with CT scans at 2 weeks and 8 months of age 
has been reported previously [11]. The severe leukoence-
phalopathy of case 1 (fig. 1) was demonstrated early in life 
during a period of ketoacidosis, whereas the diffuse atrophy 
of case 3 (fig . 3) was seen in a patient with long-stand ing, 
perhaps " end-stage " disease. Furthermore, the autopsy 
performed in case 1, 4 years after CT had demonstrated 
severe leukoencephalopathy, showed severe, diffuse, pre-
dominantly white-matter atrophy. These findings all support 
the previously advanced hypothesis that leukoencephalo-
pathy ultimately progresses to diffuse loss of white matter, 
with ventricular enlargement and eventual return of the 
remaining white matter to normal or nearly normal density 
on CT [11]. The reason for selective involvement of the 
posterior limbs of the internal capsules in cases 2 and 4 is 
unknown. 
Intravenous administration of contrast material did not 
produce any contrast enhancement or contribute to making 
a specific diagnosis (case 4) [11]. Insufficient numbers of 
CT exam inations are available to judge the possible role of 
CT in grading response to therapy. 
38 4 
ACKNOWLEDGMENT 
We thank Sandra Ressler for assistance in manuscript prepara-
tion. 
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3. Childs B, Nyhan WL, Borden M, Bard L, Cook RE. Idiopathic 
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Cerebral CT Findings in Methylmalonic and Propionic Acidemias 955

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Cerebral CT Findings in Methylmalonic and Propionic Acidemias 955

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