Clinical and genetic studies of thiamine metabolism dysfunction syndrome-4: case series and review of the literature

Abstract

Thiamine metabolism dysfunction syndrome-4 (THMD-4) is an autosomal recessive inherited rare disease (OMIM #613710) characterized by febrile illness associated episodic encephalopathy, leading to transient neurological dysfunction and progressive polyneuropathy. We report three patients from two different families with normal development, episodic encephalopathy, gait disorder, progressive chronic polyneuropathy characterized by motor difficulties, distal weakness, and hoarseness (dysphonia). We identified a homozygous missense c.576G>C, p.(Gln192His) variant in the SLC25A19 gene in both families by whole-exome sequencing. Following genetic diagnosis, thiamine replacement therapy was started, and improvement was observed in all affected patients. We highlight the associated phenotypes of an SCL25A19 mutation leading to clinical features of THMD-4.

Thiamine metabolism dysfunction syndrome type IV without encephalopathy: an atypical presentation

“…Patients usually recover completely after attacks or resolution of the precipitating factors, while some patients may have mild residual weakness. The incidence of the disease is very rare (<1 in 1,000,000) with very few cases having been reported, resulting in difficulty with clinically recognizing the disease (2). We report a case of an 8-year-old boy with THMD-4 who presented with clinical features and imaging findings characteristic of the disease but with absence of altered sensorium, further confirmed by genetic testing.…”

“…Nerve conduction studies showed motor/sensory axonal polyneuropathy. Treatment with thiamine supplementation at 400mg/day usually relieves the symptoms and needs to be continued lifelong to prevent metabolic decompensation and recurrences (2,12). Early recognition of the disease and treatment with vitamin supplementation yields better clinical outcomes, with complete recovery or residual distal myasthenia and cognitive delay (13).…”

“…The disorder is caused due to bi-allelic pathogenic variations in the solute carrier family 19 member 3 (SLC25A19) gene which encodes the mitochondrial thiamine pyrophosphate carrier. THMD-4 usually presents in developmentally normal children in the form of recurrent episodes of encephalopathy and weakness, precipitated by a febrile illness or viral infection (2). Patients usually recover completely after attacks or resolution of the precipitating factors, while some patients may have mild residual weakness.…”