Asymptomatic lesions of the basal ganglia in a patient with methylmalonic aciduria

Abstract

920Martinez-Frias, however, reported two cases of postaxial polydactyly as result of valproic acid mono therapy (one) and valproic acid in combination with carbomazepine (one) [1]. It is not clear whether these children had associated anomalies. Polydactyly must be added to the spectrum of limb defects caused by valproic acid. In our patient as in most patients also the preaxial side of the upper limb is involved. The mechanism of this predilection is unclear. References1. Martinez-Frias ML (1990) We observed a patient with M M A diagnosed at the age of 3 weeks by highly elevated urinary concentrations of methylmalonic acid (11 tool/tool creat). Enzyme studies in cultured flbroblasts indicated a rout 0 genotype. His dietary intake of natural protein was 0.8-1.2g/kg per day and carnitine was supplemented in doses of 50-100 mg/kg per day. During metabolic equilibrium urinary methylmalonic acid excretion ranged between 0.5 and 22 mol/mol creatinine (mean value = 10.5 tool/ mol creatinine, n = 14). Until 7 years of age he had nine episodes of metabolic decompensation characterised by vomiting, refusal to take oral fluids and metabolic acidosis. Laboratory findings during these episodes included mildly decompensated metabolic acidosis, plasma concentrations of ammonia and lactic acid were mildly elevated on one occasion. Urinary methylmalonic acid excretion ranged between 12 and 23 mol/mol creatinine (mean value = 17.6mol/mol creat, n = 7). A n episode at the age of 36 months was the only one to be accompanied by reduced consciousness without neurological signs. Methylmalonic acid excretion was 20mol/mol creatinine. Brain MRI at the age of 4.5 and 6.5 years revealed symmetrical lesions within the central parts of the basal ganglia (globus pallidus) (Fig. 1), These lesions were never complicated by corresponding neurological signs. There is evidence of intellectual Abbreviations: MMA = methylmalonic aciduria; OLCFA = odd numbered long-chain fatty acids

Methylmalonyl-CoA Mutase Induction by Cerebral Ischemia and Neurotoxicity of the Mitochondrial Toxin Methylmalonic Acid

“…MCM was cloned first from the liver and has been studied primarily in liver (Ledley et al, 1988(Ledley et al, , 1990Ledley, 1990;Wilkemeyer et al, 1990Wilkemeyer et al, , 1993. MCM function in brain has received less attention (Mitzen and Koeppen, 1984;Dutra et al, 1991Dutra et al, , 1993Riley et al, 1991;Dickson et al, 1994;Toyashima et al, 1995) despite the brain abnormalities that occur with MCM mutations (Gebarski et al, 1983;Matsui et al, 1983;Roodhooft et al, 1990;Gerhardt et al, 1991;Ostergaard et al, 1991;Crane et al, 1992;Stockler et al, 1992;Sum et al, 1993;Brismar and Ozand, 1994;He et al, 1995). The complete coding region from gerbil brain MCM cDNA was sequenced, along with 150 bp of 5Ј and 254 bp of 3Ј untranslated regions.…”

“…Injection of both malonate and 3-NP directly into brain produces damage to neurons and other cells (Ludolf et al, 1991(Ludolf et al, , 1992Beal et al, 1993aBeal et al, -c, 1994Fu et al, 1995a,b;Greene and Greenamyre, 1995a,b;Zeevalk et al, 1995). In people who have eaten sugar cane contaminated with 3-NP (Fu et al, 1995a,b;He et al, 1995), taken large doses of 3-NP (He et al, 1995), or have been poisoned with the mitochondrial toxin cyanide (Finelli et al, 1981;Rosenow et al, 1995), damage localized to the basal ganglia occurs that seems to be identical to the brain lesions that occur in patients with MCM mutations (Gebarski et al, 1983;Roodhooft et al, 1990;Gerhardt et al, 1991;Stockler et al, 1992;Brismar and Ozand, 1994;He et al, 1995). In culture, 3-NP acid affects neurons more than glia and can induce neuronal apoptosis (Behrens et al, 1995).…”

Methylmalonic and propionic aciduria

“…Massive accumulation of toxic metabolites (i.e., methylmalonic acid and/or its synergistically acting alternative metabolites, 2‐methylcitric acid, malonic acid, and propionyl‐CoA) causes a bioenergetic stroke due to the inhibition of the mitochondrial respiratory chain and tricarboxylic acid cycle [Kolker et al, 2003]. Globus pallidus lesions may result from long‐term poor metabolic control appearing throughout the years [Stockler et al, 1992]. Pallidal infarction with necrosis, spongiosis, and cystic cavitations, has been documented by a neuropathological study [Larnaout et al, 1998].…”

Atypical vitamin B12-unresponsive methylmalonic aciduria in a sibship with severe progressive encephalomyelopathy: A new genetic disease?

“…3). Although these findings are common in inherited metabolic disorders, they have been particularly reported in patients with methylmalonic aciduria, where the lesions are generally found in the pallidum [1,16]. Patients with propionic acidaemia surving beyond infancy have also shown abnormalities primarily involving the basal ganglia [7].…”