Episodic encephalopathy due to thiamine pyrophosphokinase deficiency is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute ... Episodic encephalopathy due to thiamine pyrophosphokinase deficiency is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (summary by Mayr et al., 2011). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).
Mayr et al. (2011) reported 5 individuals from 3 unrelated families with variable manifestations of thiamine pyrophosphokinase deficiency. Two sisters had the most severe phenotype compared to the other patients. The older sister showed developmental delay from the ... Mayr et al. (2011) reported 5 individuals from 3 unrelated families with variable manifestations of thiamine pyrophosphokinase deficiency. Two sisters had the most severe phenotype compared to the other patients. The older sister showed developmental delay from the first year of life, and lost the ability to walk after an infection-induced encephalopathic episode at age 15 months. During this episode, she had increased serum and CSF lactate. She started to walk again at 3 years of age, but continued to show muscular hypotonia and delayed psychomotor development. She had 2 further crises with encephalopathy and lactic acidosis triggered by viral infections, and died during the last crisis at the age of 8.5 years. Her sister had normal development until 18 months when she developed recurrent encephalopathic episodes associated with mildly increased CSF lactate and resulting in gait and truncal ataxia, dystonia, and eventual loss of ability to walk. She died at the age of 3.5 years during a viral infection. Both girls showed episodic increased urinary alpha-ketoglutaric acid. The second family included a brother and sister born of consanguineous Iraqi parents. Both showed normal development during the first 3 years of life, but developed progressive spasticity, dystonia, and eventual loss of gait starting at age 4. The girl lost the ability to speak, developed seizures, and was wheelchair-bound at age 11 years; however, cognition was intact. Brain MRI showed global brain atrophy and increased signal intensities in the globus pallidus, and MR spectroscopy showed a lactate peak in the basal ganglia. Urinary organic acids showed elevated alpha-ketoglutaric acid and 3-hydroxyisovaleric acid. She also had mild left ventricular hypertrophy. Her younger brother had progressive dystonia, walking difficulties, and mild microcephaly, but he had adequate cognitive development at age 7 years, and brain MRI was normal. The index patient from the third family had the mildest phenotype. Beginning at age 2 years, he had several episodes of dizziness and vertigo, as well as intermittent gait ataxia, but all episodes showed spontaneous remission. At age 10.5 years, he had a severe and prolonged episode of encephalopathy with loss of speech, headache, seizures, and extensor plantar responses, progressing to dysarthria, intention tremor, confusion, episodic ataxia, and nystagmus, and resulting in coma. Serum and CSF lactate were increased, and MRI showed changes in the white matter of the cerebellum, increased signal intensities in the corticospinal tract at the medulla oblongata, and slightly increased intensities in the dorsal pons. This episode was followed by slow regression of clinical signs in the following months. At age 17 years, he had normal mental development and attended high school; the only residual signs were dysphonia and mild paresis of the soft palate.
In 5 patients from 3 unrelated families with THMD5, Mayr et al. (2011) identified homozygous or compound heterozygous mutations in the TPK1 gene (606370.0001-606370.0005).