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A Novel Mutation in NDUFS4 Causes Leigh Syndrome in an Ashkenazi Jewish Family

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A Novel Mutation in NDUFS4 Causes Leigh Syndrome in an Ashkenazi Jewish Family J Inherit Metab Dis (2008) 31 (Suppl 2):S461–S467 DOI 10.1007/s10545-008-1049-9 SHORT REPORT A novel mutation in NDUFS4 causes Leigh syndrome in an Ashkenazi Jewish family S. L. Anderson & W. K. Chung & J. Frezzo & J. C. Papp & J. Ekstein & S. DiMauro & B. Y. Rubin Received: 15 September 2008 /Submitted in revised form: 13 November 2008 /Accepted: 19 November 2008 / Published online: 26 December 2008 # SSIEM and Springer 2008 Summary Leigh syndrome is a neurodegenerative without consanguinity with three affected children. disorder of infancy or childhood generally due to Linkage to microsatellite markers D5S1969 and mutations in nuclear or mitochondrial genes involved D5S407 led to evaluation of the complex I gene in mitochondrial energy metabolism. We performed NDUFS4, in which we identified a novel homozygous linkage analysis in an Ashkenazi Jewish (AJ) family c.462delA mutation that disrupts the reading frame. The resulting protein lacks a cAMP-dependent protein kinase phosphorylation site required for activation of Communicating editor: John Christodoulou mitochondrial respiratory chain complex I. In a Competing interests: None declared random sample of 5000 healthy AJ individuals, the References to electronic databases: Leigh syndrome: OMIM carrier frequency of the NDUFS4 mutation c.462delA 256000. NDUFS4: OMIM 602694. NDUFS4 mRNA: GenBank was 1 in 1000, suggesting that it should be considered accession # NM_002495. : : in all AJ patients with Leigh syndrome. S. L. Anderson J. Frezzo B. Y. Rubin (*) Department of Biological Sciences, Fordham University, Abbreviations 441 E. Fordham Rd., Bronx, NY 10458, USA AJ Ashkenazi Jewish e-mail: [email protected] BCS1L BCS1-like protein W. K. Chung DLD dihydrolipoamide dehydrogenase Department of Pediatrics, MRS magnetic resonance spectroscopy Columbia University Medical Center, NDUFs NADH-ubiquinone oxidoreductase New York, New York, USA Fe-S proteins and flavoproteins J. C. Papp PDHC pyruvate dehydrogenase complex Department of Human Genetics, University of California, RT-PCR reverse transcription polymerase chain Los Angeles, California, USA reaction J. Ekstein SDHA succinate dehydrogenase complex, Dor Yeshorim, The Committee for Prevention subunit A of Jewish Genetic Diseases, SURF1 surfeit 1 Brooklyn, New York, USA J. Ekstein Dor Yeshorim, The Committee for Prevention of Jewish Genetic Diseases, Introduction Jerusalem, Israel Leigh syndrome (OMIM 256000), or subacute necro- S. DiMauro tizing encephalomyelopathy, is a devastating, pae- Department of Neurology, Columbia University Medical Center, diatric neurodegenerative disorder characterized by New York, New York, USA bilateral, symmetric lesions in the brainstem, midbrain, S462 J Inherit Metab Dis (2008) 31 (Suppl 2):S461–S467 pons, thalamus, basal ganglia, and cerebellum (Leigh NM_002495). We demonstrate that the c.462delA 1951). Individuals with Leigh syndrome present with NDUFS4 mutation represents an AJ founder mutation variable clinical symptoms that include hypotonia, with a carrier frequency of approximately 1 in 1000. psychomotor retardation or regression, respiratory Identification of this AJ founder mutation should difficulties, recurrent vomiting, nystagmus, ataxia, facilitate genetic evaluation of Leigh syndrome in AJ peripheral neuropathy, external ophthalmoplegia, loss families. of vision, impaired hearing, and seizures (Loeffen et al 2000; Pitkanen et al 1996). Laboratory investigations often reveal elevated lactate levels in blood and Case reports cerebral spinal fluid. Leigh syndrome is associated with progressive neurological dysfunction and is usu- Case 1 ally lethal within the first two years of life. Biochem- ically, Leigh syndrome can result from a number of The proband, a male infant, presented at 3.5 months of inherited defects in mitochondrial energy metabolism. age with strabismus, difficulty gaining weight and Genetically, Leigh syndrome can be autosomal reces- irritability. Neurological examination showed hypoto- sive, X linked, or maternally inherited, and can result nia, head lag, ptosis and strabismus. MRI of the brain from mutations in genes encoding subunits of the demonstrated bilateral symmetrical T2 signal abnor- pyruvate dehydrogenase complex (PDHC) or subunits malities in the cerebral peduncles, red nuclei, pons and of respiratory chain complexes I, II, III, IV or V, but medulla. Magnetic resonance spectroscopy (MRS) predominantly of complexes I and IV (DiMauro and showed increased lactate and decreased N-acetylas- Schon 2001; Kirby et al 1999; Loeffen et al 2000; partic acid. MRI and MRS results suggested the Robinson 1998). Complex I is a large multiprotein diagnosis of Leigh syndrome. His prenatal history enzyme complex that transports electrons from was unremarkable. He was the product of a 41-week NADH to ubiquinone as protons are shuttled across gestation, born via normal spontaneous vaginal deliv- the inner mitochondrial membrane into the inter- ery to a 37-year-old G1P0 mother with a birth weight membrane space. Complex I is composed of seven of 3436 g and head circumference of 32 cm. His Apgar mitochondrial DNA-encoded proteins and 39 nuclear- scores were 9 and 9 at 1 and 5 minutes. At 6 months of encoded subunits (Carroll et al 2003). Mutations have age, he was admitted to the hospital for failure to been identified in all seven mitochondrial DNA- thrive and received nasogastric tube feeds. During the encoded subunits and in the nuclear genes encoding hospitalization, he was found unresponsive, required the NADH-ubiquinone oxidoreductase Fe-S proteins intubation, and could not be extubated thereafter. His and flavoproteins (NDUFs) NDUFS1, NDUFS2, clinical course was progressive and characterized by NDUFS4, NDUFS7, NDUFS8, NDUFV1 and failure to thrive and decreased gut motility that NDUFV2 (Benit et al 2001, 2003a, b; Budde et al required a gastrostomy-jejunostomy feeding tube. His 2000; Loeffen et al 1998, 2001; Petruzzella et al 2001; persistent respiratory insufficiency required a trache- Schuelke et al 1999; Triepels et al 1999; van den ostomy and ventilator support. He also developed a Heuvel et al 1998). Mutations in NDUFS1, NDUFS4, hypertrophic cardiomyopathy with moderate concen- NDUFS7, NDUFS8 and NDUFV1 have been reported tric hypertrophy and qualitatively good biventricular to cause Leigh syndrome or Leigh syndrome-like systolic function. He had recurrent unexplained fevers disease (Benit et al 2001; Budde et al 2000; Loeffen and sustained hypertension, presumably secondary to et al 1998; Petruzzella et al 2001; Schuelke et al 1999; autonomic dysfunction. Neurologically, he regressed Triepels et al 1999; van den Heuvel et al 1998), while developmentally and became less responsive and more mutations in NDUFS2 and NDUFV2 have been hypotonic despite treatment with coenzyme Q10, associated with cardiomyopathy and encephalomyop- L-carnitine, thiamine and sodium citrate. Multiple athy (Benit et al 2003a; Loeffen et al 2001). The electroencephalograms demonstrated mild to moder- identification of mutations causing complex I defects ate diffuse slowing without evidence of seizures, has been hampered by the large number of proteins in indicating an encephalopathy with diffuse cerebral this complex and by the limited understanding of the dysfunction. At 10 months of age, he died at home. role of each component. Family history at the time was unremarkable. He had a We describe an Ashkenazi Jewish (AJ) family with 13-year-old paternal half brother and a 10-year-old three affected children with Leigh syndrome and paternal half-sister who were both healthy. Both his harbouring a homozygous c.462delA mutation in parents were Ashkenazi Jews. There was no known NDUFS4 (OMIM 602694; GenBank accession no. history of consanguinity. There was no maternal or J Inherit Metab Dis (2008) 31 (Suppl 2):S461–S467 S463 Table 1 Activities of mitochondrial enzymes in skeletal muscle biopsy in a 10% muscle homogenate Enzyme Complex Activity Control activity T standard (mmol/min per g) deviation (mmol/min per g) Cytochrome-c oxidase IV 3.85 2.80 T 0.52 Succinate cytochrome-c reductase II + III 0.72 0.70 T 0.23 NADH cytochrome-c reductase I + III 0.59 1.02 T 0.38 NADH dehydrogenase I 31.36 35.48 T 7.07 Citrate synthase 17.22 9.88 T 2.55 Succinate dehydrogenase 1.67 1.00 T 0.53 paternal family history of childhood deaths, seizures, exotropia and irritability and was hypotonic. MRI of mental retardation, stroke, blindness, hearing loss, the brain demonstrated symmetric areas of signal diabetes or cardiomyopathy. hyperintensity on T2-weighted images in the cerebral His metabolic evaluation was significant for a peduncles, periaqueductal regions of the midbrain, plasma lactate that ranged from 1.0 to 9.5 mmol/L dorsal pontomedullary junction, corpus callosum, and (normal, <2.2) over a 4-month period, plasma lactate: medial globus pallidus. At 6 months of age, a gastro- pyruvate ratio of 22 (normal <25) measured simulta- stomy tube was placed to assist with feeding, and she neously when the cerebrospinal fluid lactate was 4.5 died two days later with lactic acidosis. mmol/L (normal <2.2) and cerebrospinal fluid pyru- Triplet B (case 3) presented at 6 months of age with vate was 0.17 mmol/L (normal <0.13). A muscle biopsy exotropia, hypotonia and poor head control. Unlike his at 5 months of age demonstrated a few atrophic previously two affected siblings, by 5–6 months of age fibres without ragged-red fibres, COX-deficient he was able to roll over and he was more active. He fibres, or mitochondrial
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