Epilepsy Aspects and EEG Patterns in Neuro-Metabolic Diseases

Neurometabolic diseases (NMD) are a frequent cause of epilepsy in children. Epilepsy is more frequently part of a complex clinical picture than a predominant symptom and may be of different types and various EEG patterns. The primary goal of this article is, departing from a large personal series, to describe the seizure type, EEG patterns and response to antiepileptic drugs in NMD and to discuss clinical value of epilepsy type in the setting of specific NMD. We found epilepsy was associated to NMD in 43.1%. Disorders of energy metabolism were the most frequent cause of epilepsy (61.3%). We observed generalized epilepsy in 75% of the patients with partial epilepsy in 25%. EEG was abnormal in only 71% of cases with variable patterns. Resistance to antiepileptic drugs was observed in 75% of cases. Valproate acid was incriminated in seizure worsening in 22.7% of the patients, all of them affected by mitochondriopathies.

The interplay between metabolichomeostasis and neurodegeneration:insights into the neurometabolic nature ofamyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disease that is characterized by the selectivedegeneration of upper motor neurons and lower spinal motor neurons, resulting in the progressive paralysis of allvoluntary muscles. Approximately 10 % of ALS cases are linked to known genetic mutations, with the remaining 90 %of cases being sporadic. While the primary pathology in ALS is the selective death of upper and lower motor neurons,numerous studies indicate that an imbalance in whole body and/or cellular metabolism influences the rate ofprogression of disease. This review summarizes current research surrounding the impact of impaired metabolicphysiology in ALS. We extend ideas to consider prospects that lie ahead in terms of how metabolic alterations mayimpact the selective degeneration of neurons in ALS and how targeting of adenosine triphosphate-sensitive potassium(K_(ATP)) channels may represent a promising approach for obtaining neuroprotection in ALS.

Treatment of glutaric aciduria type I(GA-I)via intracerebroventricular delivery of GCDH

Glutaric aciduria type I(GA-I)is an autosomal recessive genetic disorder caused by a deficiency in glutaryl-CoA dehydrogenase(GCDH).Patients who do not receive proper treatment may die from acute encephalopathic crisis.Current treatments for GA-I include a low-lysine diet combined with oral supplementation of L-carnitine.A mouse model of Gcdh^(c.422_428del/c.422_428del)(Gcdh^(−/−))was generated in our laboratory using CRISPR/Cas9.Gcdh^(−/−)mice had significantly higher levels of glutaric acid(GA)in the plasma,liver,and brain than those in wild-type C57BL/6 mice.When given a high-protein diet(HPD)for two days,approximately 60%of Gcdh^(−/−)mice did not survive the metabolic stress.To evaluate whether GCDH gene replacement therapy could be used to provide sustained treatment for patients with GA-1,we prepared a recombinant adeno-associated virus(rAAV)carrying a human GCDH expression cassette and injected it into Gcdh^(−/−)neonates for a proof-of-concept(PoC)study.Our study demonstrated that delivering rAAV to the central nervous system(CNS),but not the peripheral system,significantly increased the survival rate under HPD exposure.Our study also demonstrated that rAAVPHP.eB mediated a higher efficiency than that of rAAV9 in increasing the survival rate.Surviving mice showed dose-dependent GCDH protein expression in the CNS and downregulation of GA levels.Our study demonstrated that AAV-based gene replacement therapy was effective for GA-I treatment and provided a feasible solution for this unmet medical need.