Alternative titles; symbols
SNOMEDCT: 771305006; ORPHA: 217396;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17q25.1 | Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type) | 613710 | Autosomal recessive | 3 | SLC25A19 | 606521 |
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 or compound heterozygous mutation in the SLC25A19 gene (606521) on chromosome 17q25.
Amish lethal microcephaly (MCPHA; 607196) is an allelic disorder with a more severe phenotype.
Thiamine metabolism dysfunction syndrome-4 (THMD4) 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).
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.
Bottega et al. (2019) reported a patient who had a history of neurologic impairment due to acute encephalopathic events in the setting of fevers at 1 year of age. The events were characterized by tremor, hypotonia, gait difficulties, dysphagia, dysphonia, and altered consciousness. At 18 years of age, he had moderate cognitive delay, pes cavus, and atrophy of the interosseous muscles. Electromyography showed a motor and sensory neuropathy. Brain MRI showed abnormal signal in the caudate nucleus, putamen, and insula cortex.
Gowda et al. (2019) reported clinical features in a 36-month-old boy and a 5-year-old girl. The boy presented with acute weakness and encephalopathy in the setting of gastroenteritis at 11 months of age. He recovered after 3 months, but at 23 months of age and 33 months of age he had recurrent episodes of acute encephalopathy. After initiation of oral thiamine, he regained lost developmental milestones. Brain MRI showed hyperintensity of the bilateral basal ganglia and thalami. Nerve conduction studies showed axonal neuropathy. Laboratory tests demonstrated elevated serum lactate. The girl presented at 16 months of age with encephalopathy in the setting of a febrile illness. She had incomplete recovery but had another episode of encephalopathy with febrile illness at 2 years and 6 months of age. Brain MRI at 16 months of age showed hyperintensity in the basal ganglia and thalami. Nerve conduction testing showed an axonal neuropathy, which improved after thiamine supplementation.
Li et al. (2020) described 2 patients with recurrent encephalopathic episodes, abnormal signal in the putamen and caudate nucleus on brain MRI, and elevated alpha-ketoglutarate in the urine. Patient 5, aged 2 years and 10 months, and patient 6, aged 2 years and 3 months, had normal intelligence and slight motor developmental delay.
Chen et al. (2021) reported 2 sibs (patients 2 and 3) who presented with coma in the setting of influenza A infection. Brain MRI in both sibs showed abnormal signal in the basal ganglia. Both patients required mechanical ventilation but recovered spontaneous respiration. Three months after discharge and despite being started on oral thiamine, both sibs had high muscle tone, absence of speech, and occasional gaze towards sound.
Samur et al. (2022) reported 3 patients with episodic encephalopathy, abnormal gait, and polyneuropathy. Patients 1 and 2 were 11- and 13-year-old brothers, respectively. Patient 1 began having encephalopathic episodes at 2 years of age. The episodes subsequently occurred every 2 to 3 years and were triggered by respiratory tract infections. He also had dysarthria, muscle weakness, ataxia and pes equinovarus. Brain MRI showed white matter hyperintensities and necrotic degeneration of the caudate, putamen, and thalamus. Patient 2 additionally had dysphonia, seizures, muscle weakness, and areflexia. His brain MRI showed degenerative changes in the bilateral caudate nuclei. Patient 3 was a 16-year-old girl who began having encephalopathic episodes at 4 years of age. She also had ataxia, increased muscle tone, and pes equinovarus. Brain MRI showed bilateral striatal necrosis.
The transmission pattern of THMD4 in the consanguineous family reported by Spiegel et al. (2009) was consistent with autosomal recessive inheritance.
Porta et al. (2021) described response to thiamine treatment in 9 patients with THMD4, 8 of whom had previously been reported. Metabolic decompensations were recurrent and triggered by febrile episodes in the patients prior to thiamine treatment. While being treated with thiamine, none of the patients experienced an acute metabolic decompensation. One patient experienced an encephalopathic episode after discontinuing thiamine. Thiamine therapy did not improve peripheral axonal neuropathy in the 7 patients who had this clinical feature. However, in 2 patients who were treated early, peripheral neuropathy did not occur, suggesting a possible preventative effect.
Samur et al. (2022) reported outcomes in 2 symptomatic patients with THMD4 who were treated with thiamine. Patient 1 demonstrated an improvement in symptoms including axonal neuropathy and febrile episodes. Patient 2 was treated with both thiamine and baclofen and had improvement in his febrile episodes as well as achieving seizure control.
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).
In an Italian patient, born to consanguineous parents, Bottega et al. (2019) identified a homozygous mutation in the SLC25A19 gene (Q192H; 606521.0003). SLC25A19 with the Q192H mutation in HepG2 cells showed reduced expression in mitochondrial and whole cell homogenates compared to wildtype.
In 2 unrelated Indian children, born to consanguineous parents, with THMD4, Gowda et al. (2019) identified homozygous missense mutations in the SLC25A19 gene (E304K, 606521.0004; L290Q, 606521.0005). The mutations, which were found by next-generation sequencing and confirmed by Sanger sequencing, were identified in heterozygous state in both sets of parents. Functional studies were not performed.
Li et al. (2020) identified compound heterozygous mutations in the SLC25A19 gene in 2 patients with THMD4: A65V and P152T (patient 5) and A161T and A184P (patient 6). The mutations, which were identified by whole-exome sequencing and confirmed by Sanger sequencing, were identified in the carrier state in the parents.
Chen et al. (2021) identified compound heterozygous mutations in the SLC25A19 gene in 2 Chinese sibs (G26R, 606521.0006 and F249I, 606521.0007) and an unrelated Chinese child (A57T and A128V) with THMD4. Transfection of each mutation into HEK293 resulted in decreased mitochondrial thiamine pyrophosphate (TPP) compared to wildtype, indicative of deficient TPP transport.
In 2 Turkish brothers and an unrelated Turkish patient with THMD4, Samur et al. (2022) identified homozygosity for a previously reported missense mutation in the SLC25A19 gene (Q192H; 606521.0003). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing.
Bottega, R., Perrone, M. D., Vecchiato, K., Taddio, A., Sabui, S., Pecile, V., Said, H. M., Faletra, F. Functional analysis of the third identified SLC25A19 mutation causative for the thiamine metabolism dysfunction syndrome 4. J. Hum. Genet. 64: 1075-1081, 2019. [PubMed: 31506564] [Full Text: https://doi.org/10.1038/s10038-019-0666-5]
Chen, Y., Fang, B., Hu, X., Guo, R., Guo, J., Fang, K., Ni, J., Li, W., Qian, S., Hao, C. Identification and functional analysis of novel SLC25A19 variants causing thiamine metabolism dysfunction syndrome 4. Orphanet J. Rare Dis. 16: 403, 2021. [PubMed: 34587972] [Full Text: https://doi.org/10.1186/s13023-021-02028-4]
Gowda, V. K., Srinivasan, V. M., Jehta, K., Bhat, M. D. Bilateral striatal necrosis with polyneuropathy with a novel SLC25A19 (mitochondrial thiamine pyrophosphate carrier OMIM*606521) mutation: treatable thiamine metabolic disorder--a report of two Indian cases. Neuropediatrics 50: 313-317, 2019. [PubMed: 31295743] [Full Text: https://doi.org/10.1055/s-0039-1693148]
Li, D., Song, J., Li, X., Liu, Y., Dong, H., Kang, L., Liu, Y., Zhang, Y., Jin, Y., Guan, H., Zhou, C., Yang, Y. Eleven novel mutations and clinical characteristics in seven Chinese patients with thiamine metabolism dysfunction syndrome. Europ. J. Med. Genet. 63: 104003, 2020. [PubMed: 32679198] [Full Text: https://doi.org/10.1016/j.ejmg.2020.104003]
Porta, F., Siri, B., Chiesa, N., Ricci, F., Nika, L., Sciortino, P., Spada, M. SLC25A19 deficiency and bilateral striatal necrosis with polyneuropathy: a new case and review of the literature. J. Pediat. Endocr. Metab. 34: 261-266, 2021. [PubMed: 33544541] [Full Text: https://doi.org/10.1515/jpem-2020-0139]
Samur, B. M., Gumus, G., Canpolat, M., Gumus, H., Per, H., Caglayan, A. O. Clinical and genetic studies of thiamine metabolism dysfunction syndrome-4: case series and review of the literature. Clin. Dysmorph. 31: 125-131, 2022. [PubMed: 35102031] [Full Text: https://doi.org/10.1097/MCD.0000000000000411]
Spiegel, R., Shaag, A., Edvardson, S., Mandel, H., Stepensky, P., Shalev, S. A., Horovitz, Y., Pines, O., Elpeleg, O. SLC25A19 mutation as a cause of neuropathy and bilateral striatal necrosis. Ann. Neurol. 66: 419-424, 2009. [PubMed: 19798730] [Full Text: https://doi.org/10.1002/ana.21752]