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Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations.

Invernizzi F, Ardissone A, Lamantea E, Garavaglia B, Zeviani M, Farina L, Ghezzi D, Moroni I - Front Genet (2014)

Bottom Line: Biochemical findings include defects of complexes I, II, and III of the mitochondrial respiratory chain and severe deficiency of Pyruvate dehydrogenase complex (PDHc).We describe an Italian male patient presenting with severe psychomotor regression after an infectious episode, lactic acidosis, hyperglycinemia, reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity.He carried two heterozygous mutations in NFU1, one novel (p.Cys210Phe) and one previously reported (p.Gly189Arg) missense change affecting highly conserved residues.

View Article: PubMed Central - PubMed

Affiliation: Unit of Molecular Neurogenetics, Istituto Neurologico "Carlo Besta," Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Milan, Italy.

ABSTRACT
Multiple Mitochondrial Dysfunction Syndrome (MMDS) comprises a group of severe autosomal recessive diseases with onset in early infancy and characterized by a systemic disorder of energy metabolism, resulting in weakness, respiratory failure, lack of neurological development, lactic acidosis, and early death. Biochemical findings include defects of complexes I, II, and III of the mitochondrial respiratory chain and severe deficiency of Pyruvate dehydrogenase complex (PDHc). Three genes have been associated with MMDS since now: NFU1, BOLA3, and IBA57. We describe an Italian male patient presenting with severe psychomotor regression after an infectious episode, lactic acidosis, hyperglycinemia, reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity. He carried two heterozygous mutations in NFU1, one novel (p.Cys210Phe) and one previously reported (p.Gly189Arg) missense change affecting highly conserved residues. A severe leukoencephalopathy with cavitations in deep white matter was disclosed at brain MRI, suggesting a peculiar neuroradiological phenotype associated with defect in this gene.

No MeSH data available.


Related in: MedlinePlus

Brain MRI. Axial T2 (A-C) and FLAIR images (D-F) show diffuse hyper intensity of the white matter (A: asterisks) more prominent in the posterior periventricular and deep regions (A-C: arrows) with evidence of partial cystic degeneration and cavitations in FLAIR sections (D-F: arrows).
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Figure 1: Brain MRI. Axial T2 (A-C) and FLAIR images (D-F) show diffuse hyper intensity of the white matter (A: asterisks) more prominent in the posterior periventricular and deep regions (A-C: arrows) with evidence of partial cystic degeneration and cavitations in FLAIR sections (D-F: arrows).

Mentions: The proband was the first child born from unrelated Italian parents. Family history was negative; pregnancy and delivery were uneventful. Psychomotor development was referred normal until 7 months of age. During a mild febrile illness, he presented severe and rapid psychomotor regression, loosing sitting position and smiling, and developed spastic tetraparesis. Metabolic exams revealed high plasma lactate (5620 mmol/L; nv 580–2100 mmol/L) and pyruvate levels (294 mmol/L; nv 55–145), abnormal urinary excretion of lactic, succinic, fumaric, and glutaric acids; plasma amino acids analysis disclosed elevation of glycine (589 mmol/l, nv 11–360). Brain MRI showed the presence of a diffuse and symmetric involvement of hemispheric white matter with more marked abnormalities in the deep white matter that presented also cavitations (Figure 1). The cerebellum, brainstem and basal ganglia had normal appearance, while spectroscopy revealed a peak of lactic acid and decreased N-acetyl Aspartate/creatine ratio.


Cavitating leukoencephalopathy with multiple mitochondrial dysfunction syndrome and NFU1 mutations.

Invernizzi F, Ardissone A, Lamantea E, Garavaglia B, Zeviani M, Farina L, Ghezzi D, Moroni I - Front Genet (2014)

Brain MRI. Axial T2 (A-C) and FLAIR images (D-F) show diffuse hyper intensity of the white matter (A: asterisks) more prominent in the posterior periventricular and deep regions (A-C: arrows) with evidence of partial cystic degeneration and cavitations in FLAIR sections (D-F: arrows).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4238403&req=5

Figure 1: Brain MRI. Axial T2 (A-C) and FLAIR images (D-F) show diffuse hyper intensity of the white matter (A: asterisks) more prominent in the posterior periventricular and deep regions (A-C: arrows) with evidence of partial cystic degeneration and cavitations in FLAIR sections (D-F: arrows).
Mentions: The proband was the first child born from unrelated Italian parents. Family history was negative; pregnancy and delivery were uneventful. Psychomotor development was referred normal until 7 months of age. During a mild febrile illness, he presented severe and rapid psychomotor regression, loosing sitting position and smiling, and developed spastic tetraparesis. Metabolic exams revealed high plasma lactate (5620 mmol/L; nv 580–2100 mmol/L) and pyruvate levels (294 mmol/L; nv 55–145), abnormal urinary excretion of lactic, succinic, fumaric, and glutaric acids; plasma amino acids analysis disclosed elevation of glycine (589 mmol/l, nv 11–360). Brain MRI showed the presence of a diffuse and symmetric involvement of hemispheric white matter with more marked abnormalities in the deep white matter that presented also cavitations (Figure 1). The cerebellum, brainstem and basal ganglia had normal appearance, while spectroscopy revealed a peak of lactic acid and decreased N-acetyl Aspartate/creatine ratio.

Bottom Line: Biochemical findings include defects of complexes I, II, and III of the mitochondrial respiratory chain and severe deficiency of Pyruvate dehydrogenase complex (PDHc).We describe an Italian male patient presenting with severe psychomotor regression after an infectious episode, lactic acidosis, hyperglycinemia, reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity.He carried two heterozygous mutations in NFU1, one novel (p.Cys210Phe) and one previously reported (p.Gly189Arg) missense change affecting highly conserved residues.

View Article: PubMed Central - PubMed

Affiliation: Unit of Molecular Neurogenetics, Istituto Neurologico "Carlo Besta," Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Milan, Italy.

ABSTRACT
Multiple Mitochondrial Dysfunction Syndrome (MMDS) comprises a group of severe autosomal recessive diseases with onset in early infancy and characterized by a systemic disorder of energy metabolism, resulting in weakness, respiratory failure, lack of neurological development, lactic acidosis, and early death. Biochemical findings include defects of complexes I, II, and III of the mitochondrial respiratory chain and severe deficiency of Pyruvate dehydrogenase complex (PDHc). Three genes have been associated with MMDS since now: NFU1, BOLA3, and IBA57. We describe an Italian male patient presenting with severe psychomotor regression after an infectious episode, lactic acidosis, hyperglycinemia, reduction of respiratory chain complex II associated with a marked deficiency of PDHc activity. He carried two heterozygous mutations in NFU1, one novel (p.Cys210Phe) and one previously reported (p.Gly189Arg) missense change affecting highly conserved residues. A severe leukoencephalopathy with cavitations in deep white matter was disclosed at brain MRI, suggesting a peculiar neuroradiological phenotype associated with defect in this gene.

No MeSH data available.


Related in: MedlinePlus