Fumarase Deficiency: A Safe and Potentially Disease Modifying Effect of High Fat/Low Carbohydrate Diet

Abstract

Fumarate hydratase deficiency (FHD) caused by biallelic alterations of the FH (fumarate hydratase) gene is a rare disorder of the tricarboxylic acid cycle, classically characterized by encephalopathy, profound psychomotor retardation, seizures, a spectrum of brain abnormalities and early death in childhood. Less common milder phenotypes with moderate cognitive impairment and long-term survival have been reported. In addition, heterozygous mutations of the FH gene are responsible for hereditary leiomyomatosis and renal cell cancer (HLRCC). There is currently no recommended disease modifying treatment for FHD and only isolated reports of unsuccessful dietary modifications. Herein, we describe the safe and possibly disease modifying effect of a high fat, low carbohydrate diet in a 14-year-old female with severe FHD.

Fumarase Deficiency: A Case With a New Pathogenic Mutation and a Review of the Literature

“…Interestingly a few patients were reported with macrocephaly, probably because of enlarged ventricles. 6,14,15…”

“…Another characteristic of FD is axial hypotonia 5 -8,14,17 -27,30,32 -35 and hypertonia of the limbs. 2,4,16…”

“…Thus, neuroradiological imaging may reveal polymicrogyria 4,6,7,14,15,23 enlarged ventricles 2,4,5,12,13,15 -17,27,34 agenesis or hypoplasia of the corpus callosum 5,7,9,13,21,22,29 and white matter abnormalities such as hypomyelination, delayed myelination, and demyelination are frequently seen. 5,6,14,18,21,22,24,26 EEG frequently reveals diffuse slowing of background activity with spike waves or hypsarrhythmia 5,12,14,16,19 -21,25,27,31,34 as in our patient (Figure 2). Notably, patients with pyruvate dehydrogenase deficiency, which are also affected by impaired energy production via the Krebs cycle, also frequently present with similar craniofacial dysmorphisms.…”

“…31 Interestingly, some patients have a milder phenotype and although they are developmentally delayed, they are able to sit and walk with assistance. 7,14,22,36…”

“…However in the published cases dysmorphic features were observed in homozygous patients with consanguineous parents 5,9 and with nonconsanguineous parents 15,23 as well as in heterozygous patients with nonconsanguineous parents. 12,18,21,29 Moreover, there were as many homozygous patients without dysmorphic features that were homozygote 2,5,7,8,11,17,19,20,25 as there were compound heterozygous patients 13,14,16,30,31 (Table 1).…”