Infantile Leigh-like syndrome caused by SLC19A3 mutations is a treatable disease

Inherited disorders of oxidative phosphorylation cause the clinically and genetically heterogeneous diseases known as mitochondrial energy generation disorders, or mitochondrial diseases. Over the last three decades, mutations causing these disorders have been identified in almost 290 genes, but many patients still remain without a molecular diagnosis. Moreover, while knowledge of the genetic causes is continually expanding, understanding into how these defects lead to cellular dysfunction and organ pathology is still incomplete. Here, we review recent developments in disease gene discovery, functional characterization, and shared pathogenic parameters influencing disease pathology that offer promising avenues towards development of effective therapies.Mitochondrial energy generation disorders (hereafter termed mitochondrial diseases) are a heterogeneous group of rare disorders involving defective oxidative phosphorylation (OXPHOS). The OXPHOS system comprises five enzyme complexes, situated in the mitochondrial inner membrane. The first four complexes and two electron carriers form the respiratory chain, which generates a proton gradient used by complex V (F 1 F o ATP synthase) to generate the majority of cellular ATP. For the purpose of this review, we have focused on genes and mechanisms that have a demonstrated defect in primary energy generation (e.g. components of the OXPHOS system) or a clear expected role in mitochondrial homeostasis and the ability to generate energy (e.g. components of the TCA cycle and pyruvate dehydrogenase complex (PDC) that feed into OXPHOS, or those affecting mitochondrial membranes and structure).

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“…ATAD3A and SLC25A46). In others, it has led to a treatment, as in the case of biotin and thiamine supplementation in SLC19A3 mutations (94).…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

Frazier

Thorburn

Compton

2019

Journal of Biological Chemistry

201

223

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“…The distinctive feature of this rare disease is a potential effectiveness of the treatment with biotin and thiamine in high doses [3,5,18]. Pathogenic variants in the SLC19A3 [NM_025243.3] coding for thiamine transporter 2 lead to a decrease in the free-thiamine concentration in cells [10].…”

Section: Introductionmentioning

confidence: 99%

“…Pathogenic variants in the SLC19A3 [NM_025243.3] coding for thiamine transporter 2 lead to a decrease in the free-thiamine concentration in cells [10]. Brain imaging most commonly shows a basal ganglia involvement of Leigh-like syndrome type [4,5,15] and/or Wernicke encephalopathy features resembling acquired vitamin B 1 deficiency [7]. Progressive brain atrophy is a relatively common finding [15].…”

Section: Introductionmentioning

confidence: 99%

Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease

Pronicki¹,

Piekutowska‐Abramczuk²,

Jurkiewicz³

et al. 2017

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“…Therefore, they propose to rename BBGD to BTBGD (biotin-thiamine-responsive basal ganglia disease) as the addition of thiamine is clearly essential. It is highly suggestive, as illustrated in these studies and put forward by Haack et al (2014) that the combination of biotin and thiamine is most effective.…”

Section: Sirmentioning

confidence: 86%

“…The letter by Haack et al (2014) provides important information confirming the role of the thiamine transporter hTHTR2 in Leigh syndrome and the beneficial effect of biotin and/or thiamine treatment for patients harbouring mutations in the gene encoding hTHTR2, SLC19A3. In recent years many new pathogenic mutations have been reported in SLC19A3 resulting in several age-related neurological phenotypes like biotin-responsive basal ganglia disease (BBGD), Wernicke-like encephalopathy and Leigh syndrome and various responses to biotin and/or thiamine (Zeng et al, 2005;Kono et al, 2009;Debs et al, 2010;Yamada et al, 2010).…”

Section: Sirmentioning

confidence: 90%

Reply: Infantile Leigh-like syndrome caused by SLC19A3 mutations is a treatable disease

Gerards

Coo

Smeets

2014

Brain

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Infantile Leigh-like syndrome caused by SLC19A3 mutations is a treatable disease

Cited by 39 publications

References 7 publications

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

Mitochondrial energy generation disorders: genes, mechanisms, and clues to pathology

Neuropathological characteristics of the brain in two patients with SLC19A3 mutations related to the biotin-thiamine-responsive basal ganglia disease

Reply: Infantile Leigh-like syndrome caused by SLC19A3 mutations is a treatable disease

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