An 18-month-old male presents with a two-day history of increasing lethargy,anorexia, and vomiting. On physical examination, he was found to be dehydratedand hypotonic, and was responsive only to painful stimuli. Kussmaul'srespirations were noted, and admission blood gases revealed metabolic acidosis(arterial pH of 7.24). Serum chemistries revealed a serum ammonia level of 147umole/l. The patient's urine contained a large amount of ketones, and hislevels of methylmalonic acid were elevated to 144 mmole/mole of creatinine. CSFanalysis was normal. An unenhanced CT scan of the brain (figure 1) and an MRstudy (figures 2 and 3) were obtained at one and seven days followingpresentation, respectively.

DIAGNOSIS:

Methylmalonic acidemia.

DISCUSSION:

Methylmalonic acidemia (MMA) is a disorder of organic acid metabolism. Itconsists of a group of genetically distinct autosomal recessive disorders thataffect the conversion of methylmalonyl-CoA to succinyl-CoA withaccumulation of MMA in blood and urine.1 Long term clinical management includesdietary protein restriction and cobalamin supplementation. In clinicalexacerbations, laboratory findings can include methylmalonic acidemia andaciduria, ketonuria, ammonemia, and metabolic acidosis. The associatedketoacidosis leads to hypotonia, dehydration, and respiratory distress, and maybe complicated by acute neurologic manifestations including lethargy,irritability, and convulsions.2,3 Acute bilateral necrosis of the globi pallidiproduces extrapyramidal symptoms, primarily manifesting as dystonia. Necrosismay also involve the internal capsule, and can produce symptoms ofcorticospinal and corticobulbar tract involvement.3

In the acute phase, CT will demonstrate non-enhancing bilateralhypodensities in the globi pallidi (figure 1); however, enhancement of theglobi pallidi may be seen in the subacute phase.3 Diffuse cerebral white matterhypodensity also has been reported in two cases.4 MR demonstrates cytotoxicedema in the pallidal nuclei during the acute phase, characterized by lowsignal intensity on T1-weighted images and high signal intensity on T2-weightedimages (figure 2).5 MR may demonstrate peripheral pallidal enhancement earlierthan has been reported with CT, as documented in our case during the acutephase of the illness (figure 3). No obvious correlation between the severity ofthe disease and basal ganglia involvement has been reported. Brismar and Pinar6reported that widening of the sulci and fissures may be seen during the firstyear of life, while delayed myelination may be noted during the second year oflife. Both abnormalities may subside with age.6

The radiologic differential diagnosis of methylmalonic acidemia includesother disorders associated with bilateral necrosis of the basal gangliaincluding carbon monoxide, cyanide, and methanol poisoning; Leigh'sdisease (subacute necrotizing leukoencephalopathy); and propionic acidemia. Anappropriate history should be sufficient, however, to rule out a diagnosis ofcarbon monoxide, cyanide, or methanol poisoning. Symmetric necrosis of theputamen is the characteristic finding in Leigh's disease. Lesions also arecommonly found in the globi pallidi and the caudate nucleus, but almost neverin the absence of putaminal abnormalities. Leigh's disease also mayinvolve the brainstem, periaqueductal region, thalamus, and paraventricularwhite matter.7,8 Although MMA and propionic acidemia cannot be distinguishedradiographically, analysis of urine and plasma for organic acids candistinguish between the two disorders.4

References

1. Korf B, Wallman JK, Levy HL: Bilateral lucency of the globus palliduscomplicating methylmalonic acidemia. Ann Neurol 20:364-366, 1986.

2. Matsui SM, Mahoney MJ, Rosenberg LE: The natural history of the inheritedmethylmalonic acidemias. N Engl J Med 308:857-861, 1983.

3. Heidenreich R, Natowcz M, Hainline B, Berman P: Acute extrapyramidalsyndrome in methylmalonic acidemia: "Metabolic stroke" involving theglobus pallidus. J Pediatr 113:1022-1027, 1988.

4. Gebarski SS, Gabrielsen TO, Knake JE, Latack JT: Cerebral CT findings inmethymalonic and propionic acidemias. AJNR 4:955-957, 1983.

5. Andreula CF, Blasi RD, Carella A: CT and MR studies of methylmalonicacidemia. AJNR 12:410-412, 1991.

6. Brismar J, Pinar OT: CT and MR of the brain in disorders of thepropionate and methylmalonate metabolism. AJNR 15:1459-1473, 1994.

7. Medina L, Chi TL, DeVivo DC, Hilal SK: MR findings in patients withsubacute necrotizing encephalomyelopathy: correlation with biochemical defect.AJNR 11:379-384, 1990.

8. Heckkmann JM, Eastman R, Handler L: Leigh disease: MR documentation ofthe evolution of an acute attack. AJNR 14:1157-1159, 1993.

Prepared by Manoj Bhatia, MD, Radiological Associates of Central Florida,Leesburg, FL, Joel Curé, MD and Pamela Van Tassel, MD, MedicalUniversity of South Carolina, Charleston, SC.