Thiamine Metabolism Dysfunction Syndrome 4 (Bilateral Striatal Degeneration And Progressive Polyneuropathy Type)

A number sign (#) is used with this entry because thiamine metabolism dysfunction syndrome-4 (THMD4), also known as bilateral striatal degeneration and progressive polyneuropathy, is caused by homozygous mutation in the SLC25A19 gene (606521) on chromosome 17q25.

Amish lethal microcephaly (MCPHA; 607196) is an allelic disorder with a more severe phenotype.

Description

Thiamine metabolism dysfunction syndrome-4 is an autosomal recessive metabolic disorder characterized by childhood onset of episodic encephalopathy, often associated with a febrile illness, and causing transient neurologic dysfunction. Most patients recover fully, but some may have mild residual weakness. Affected individuals also develop a slowly progressive axonal polyneuropathy beginning in childhood. Brain imaging during the acute episodes shows lesions consistent with bilateral striatal degeneration or necrosis (summary by Spiegel et al., 2009).

For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).

Clinical Features

Spiegel et al. (2009) reported a consanguineous Arab Muslim family in which 4 sibs had a disorder characterized by acute encephalopathic episodes associated with striatal necrosis on brain imaging as well as a progressive chronic polyneuropathy. All patients had normal early psychomotor development, with onset of episodic acute encephalopathic episodes in childhood between ages 3.5 and 6.5 years. These episodes were associated with nonspecific febrile illness and were characterized by lethargy, muscle weakness resulting in paralysis, areflexia, and dysarthria. These episodes were followed by complete resolution and no loss of psychomotor development, although most had residual mild distal weakness. Laboratory investigations showed mild increased lactate in the cerebrospinal fluid (CSF) during the acute phase, and brain imaging showed bilateral multiple T2-hyperintense lesions in the caudate and putamen, with sparing of the globus pallidus. In addition to encephalopathic episodes, all sibs had childhood onset of progressive chronic polyneuropathy characterized by motor difficulties, frequent falls, and distal weakness and atrophy of the lower limbs, accompanied by lower limb contractures and foot deformities. Electrophysiologic studies showed an axonal motor neuropathy. All sibs had age-appropriate cognition at ages 7 to 20 years.

Inheritance

The inheritance pattern in the consanguineous family reported by Spiegel et al. (2009) was consistent with autosomal recessive.

Molecular Genetics

By homozygosity mapping followed by candidate gene analysis of a consanguineous Arab Muslim family with bilateral striatal necrosis and progressive polyneuropathy, Spiegel et al. (2009) identified a homozygous mutation in the SLC25A19 gene (G125S; 606521.0002).