Mitochondrial Dysfunction in a Patient with Joubert Syndrome

Abstract

Joubert syndrome is a genetically heterogeneous disorder. The diagnostic criteria include episodic hyperventilation, abnormal eye movements, psychomotor retardation, hypotonia, ataxia, and the characteristic neuro-imaging findings (molar-tooth sign). Many of these clinical features have been observed in new-borns with mitochondrial disorders as well. Congenital brain malformations, including cerebellar hypoplasia, have been described in pyruvate dehydrogenase deficiency. Malformations of the vermis and the cerebellar peduncles, with the lack of axonal decussations, however, are characteristic for Joubert syndrome but unique in patients with mitochondrial disorders. Here, we describe a child with Joubert syndrome presenting with primary lactic acidemia, decreased pyruvate oxidation rates, decreased ATP production, and a mildly decreased pyruvate dehydrogenase complex activity measured in a fresh muscle biopsy. Sequence analysis of the PDHc E1 alpha gene and the PDHX genes revealed no mutations. The patient received continuous feeding through a feeding tube for two years and showed a significant clinical improvement with a complete resolution of the chronic lactic acidemia. A second muscle biopsy revealed significantly decreased pyruvate oxidation rates and ATP production, but a normal pyruvate dehydrogenase complex activity. We suggest that the described mitochondrial dysfunction in our patient is secondary to an underlying mutation leading to Joubert syndrome.

Joubert syndrome - vermis hypoplasia - lactic acidemia - decreased PDHc activity

References

• 1 Aynaci F M, Mocan H, Bahadir S, Sari A, Aksoy A. A case of Menkes' syndrome associated with deafness and inferior cerebellar vermian hypoplasia.  Acta Paediatr. 1997;  86 121-123
• 2 Bentlage H A, Wendel U, Schagger H, ter Laak H J, Janssen A J, Trijbels J M. Lethal infantile mitochondrial disease with isolated complex I deficiency in fibroblasts but with combined complex I and IV deficiencies in muscle.  Neurology. 1996;  47 243-248
• 3 Boltshauser E, Isler W. Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis.  Neuropaediatrie. 1977;  8 57-66
• 4 Brown R M, Head R A, Brown G K. Pyruvate dehydrogenase E3 binding protein deficiency.  Hum Genet. 2002;  110 187-191
• 5 Brown R M, Head R A, Boubriak I I, Leonard J V, Thomas N H, Brown G K. Mutations in the gene for the E1-beta subunit: a novel cause of pyruvate dehydrogenase deficiency.  Hum Genet. 2004;  115 123-127
• 6 Ferland R J, Eyaid W, Collura R V, Tully L D, Hill R S. et al . Abnormal cerebellar development and axonal decussation due to mutations in AHI1 in Joubert syndrome.  Nature Genet. 2004;  36 1008-1013
• 7 Lib M Y, Brown R M, Brown G K, Marusich M F, Capaldi R A. Detection of pyruvate dehydrogenase E1 alpha-subunit deficiencies in females by immunohistochemical demonstration of mosaicism in cultured fibroblasts.  J Histochem Cytochem. 2002;  50 877-884
• 8 Michotte A, De Meirleir L, Lissens W, Denis R, Wayenberg J L, Liebaers I. et al . Analysis of pyruvate dehydrogenase expression in embryonic mouse brain: localization and developmental regulation.  Brain Res Dev Brain Res. 1994;  77 63-76
• 9 Pfeiffer R A. The Joubert syndrome associated with bilateral chorioretinal coloboma.  Europ J Pediat. 1981;  137 101-102
• 10 Smeitink J, Sengers R, Trijbels F, van den Heuvel L. Human NADH: ubiquinone oxidoreductase.  J Bioenerg Biomembr. 2001;  33 259-266
• 11 Takanashi J, Fujii K, Sugita K, Kohno Y. Neuroradiologic findings in glutaric aciduria type II.  Pediatr Neurol. 1999;  20 142-145
• 12 Wakakura M, Hatono N, Tateno S. Cerebello-oculo-hepato-renal syndrome with possible mitochondrial dysfunction.  Jpn J Ophthalmol. 1993;  37 62-69

1 The authors contributed equally to this work