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Thiamine pyrophosphokinase deficiency causes a Leigh Disease like phenotype in a sibling pair: identification through whole exome sequencing and management strategies

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ABSTRACT

We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones. The diagnosis of TPK deficiency was difficult due to inconsistent biochemical and diagnostic parameters, rapidity of clinical demise and would not have been made in a timely manner without the use of whole exome sequencing. Molecular diagnosis allowed for attempt at dietary modification with cofactor supplementation which resulted in an improved clinical course.

No MeSH data available.


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MRI findings in sibling pair with TPK deficiency.A–C, MRI of Patient 1 at 11 months of age. Axial FLAIR (A), proton density (B) and T2 (C) images at the level of the thalamus. The images demonstrate increased signals in the posterior aspect of the putamen bilaterally (large arrowheads), and subtle changes in the ventrolateral thalamus (small arrowhead, C). Myelination was normal for age.D–F, MRI of Patient 1 at 28 months. Axial FLAIR images at the level of the lower pons (D), the midbrain (E), and the thalami (F). Increasing T2 signal abnormalities have developed, involving bilateral caudate, putamen, globus pallidus, thalami and optic radiations (arrowhead, F). The corticospinal tracts traveling through the midbrain, pons and medulla are involved (arrowheads, D and E), with additional abnormal signals in the posterior pontine tracks and deep cerebellum (D). Restricted diffusion with signal changes was present in the caudate, putamen and globus pallidus, as well as parts of the thalami and corticospinal tract (not illustrated).G–I, MRI of Patient 2 at 12 months of age. Axial T2 FLAIR (G), spin echo proton density (H) and T2 (I) images. The extent of myelination is advanced for age. Abnormal hyperintense T2 signal is evident in the posterior putamina and thalami (arrowheads) bilaterally. Abnormal signal in the dentate nuclei was present (not illustrated). MR Spectroscopy over the basal ganglia demonstrated nonspecific increase in the choline to creatine ratio with no lactate peak, and diffusion images were normal (not illustrated). Findings are similar in pattern and distribution to his sibling's.
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f0005: MRI findings in sibling pair with TPK deficiency.A–C, MRI of Patient 1 at 11 months of age. Axial FLAIR (A), proton density (B) and T2 (C) images at the level of the thalamus. The images demonstrate increased signals in the posterior aspect of the putamen bilaterally (large arrowheads), and subtle changes in the ventrolateral thalamus (small arrowhead, C). Myelination was normal for age.D–F, MRI of Patient 1 at 28 months. Axial FLAIR images at the level of the lower pons (D), the midbrain (E), and the thalami (F). Increasing T2 signal abnormalities have developed, involving bilateral caudate, putamen, globus pallidus, thalami and optic radiations (arrowhead, F). The corticospinal tracts traveling through the midbrain, pons and medulla are involved (arrowheads, D and E), with additional abnormal signals in the posterior pontine tracks and deep cerebellum (D). Restricted diffusion with signal changes was present in the caudate, putamen and globus pallidus, as well as parts of the thalami and corticospinal tract (not illustrated).G–I, MRI of Patient 2 at 12 months of age. Axial T2 FLAIR (G), spin echo proton density (H) and T2 (I) images. The extent of myelination is advanced for age. Abnormal hyperintense T2 signal is evident in the posterior putamina and thalami (arrowheads) bilaterally. Abnormal signal in the dentate nuclei was present (not illustrated). MR Spectroscopy over the basal ganglia demonstrated nonspecific increase in the choline to creatine ratio with no lactate peak, and diffusion images were normal (not illustrated). Findings are similar in pattern and distribution to his sibling's.

Mentions: Cerebral MRI at 12 months of age demonstrated T2 bright abnormalities (Fig. 1, A–C) in the basal ganglia and thalami. Repeat MRI during her metabolic collapse at 28 months revealed progressive findings suggestive of mitochondrial disease (Fig. 1, D–F).


Thiamine pyrophosphokinase deficiency causes a Leigh Disease like phenotype in a sibling pair: identification through whole exome sequencing and management strategies
MRI findings in sibling pair with TPK deficiency.A–C, MRI of Patient 1 at 11 months of age. Axial FLAIR (A), proton density (B) and T2 (C) images at the level of the thalamus. The images demonstrate increased signals in the posterior aspect of the putamen bilaterally (large arrowheads), and subtle changes in the ventrolateral thalamus (small arrowhead, C). Myelination was normal for age.D–F, MRI of Patient 1 at 28 months. Axial FLAIR images at the level of the lower pons (D), the midbrain (E), and the thalami (F). Increasing T2 signal abnormalities have developed, involving bilateral caudate, putamen, globus pallidus, thalami and optic radiations (arrowhead, F). The corticospinal tracts traveling through the midbrain, pons and medulla are involved (arrowheads, D and E), with additional abnormal signals in the posterior pontine tracks and deep cerebellum (D). Restricted diffusion with signal changes was present in the caudate, putamen and globus pallidus, as well as parts of the thalami and corticospinal tract (not illustrated).G–I, MRI of Patient 2 at 12 months of age. Axial T2 FLAIR (G), spin echo proton density (H) and T2 (I) images. The extent of myelination is advanced for age. Abnormal hyperintense T2 signal is evident in the posterior putamina and thalami (arrowheads) bilaterally. Abnormal signal in the dentate nuclei was present (not illustrated). MR Spectroscopy over the basal ganglia demonstrated nonspecific increase in the choline to creatine ratio with no lactate peak, and diffusion images were normal (not illustrated). Findings are similar in pattern and distribution to his sibling's.
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f0005: MRI findings in sibling pair with TPK deficiency.A–C, MRI of Patient 1 at 11 months of age. Axial FLAIR (A), proton density (B) and T2 (C) images at the level of the thalamus. The images demonstrate increased signals in the posterior aspect of the putamen bilaterally (large arrowheads), and subtle changes in the ventrolateral thalamus (small arrowhead, C). Myelination was normal for age.D–F, MRI of Patient 1 at 28 months. Axial FLAIR images at the level of the lower pons (D), the midbrain (E), and the thalami (F). Increasing T2 signal abnormalities have developed, involving bilateral caudate, putamen, globus pallidus, thalami and optic radiations (arrowhead, F). The corticospinal tracts traveling through the midbrain, pons and medulla are involved (arrowheads, D and E), with additional abnormal signals in the posterior pontine tracks and deep cerebellum (D). Restricted diffusion with signal changes was present in the caudate, putamen and globus pallidus, as well as parts of the thalami and corticospinal tract (not illustrated).G–I, MRI of Patient 2 at 12 months of age. Axial T2 FLAIR (G), spin echo proton density (H) and T2 (I) images. The extent of myelination is advanced for age. Abnormal hyperintense T2 signal is evident in the posterior putamina and thalami (arrowheads) bilaterally. Abnormal signal in the dentate nuclei was present (not illustrated). MR Spectroscopy over the basal ganglia demonstrated nonspecific increase in the choline to creatine ratio with no lactate peak, and diffusion images were normal (not illustrated). Findings are similar in pattern and distribution to his sibling's.
Mentions: Cerebral MRI at 12 months of age demonstrated T2 bright abnormalities (Fig. 1, A–C) in the basal ganglia and thalami. Repeat MRI during her metabolic collapse at 28 months revealed progressive findings suggestive of mitochondrial disease (Fig. 1, D–F).

View Article: PubMed Central - PubMed

ABSTRACT

We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones. The diagnosis of TPK deficiency was difficult due to inconsistent biochemical and diagnostic parameters, rapidity of clinical demise and would not have been made in a timely manner without the use of whole exome sequencing. Molecular diagnosis allowed for attempt at dietary modification with cofactor supplementation which resulted in an improved clinical course.

No MeSH data available.


Related in: MedlinePlus