<i>NDUFV1</i> mutations in complex I deficiency: Case reports and review of symptoms

Zanette, Vanessa; Valle, Daniel do; Telles, Bruno Augusto; Robinson, Alan J.; Monteiro, Vaneisse; Santos, Mara Lucia S. F.; Souza, Ricardo Lehtonen R.; Benincá, Cristiane

doi:10.1590/1678-4685-GMB-2021-0149

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Genetics and Molecular Biology

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Human and Medical Genetics • Genet. Mol. Biol. 44 (4) • 2021 • https://doi.org/10.1590/1678-4685-GMB-2021-0149 copy

NDUFV1 mutations in complex I deficiency: Case reports and review of symptoms

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Mitochondrial complex I (CI) deficiency is the most common oxidative phosphorylation disorder described. It shows a wide range of phenotypes with poor correlation within genotypes. Herein we expand the clinics and genetics of CI deficiency in the brazilian population by reporting three patients with pathogenic (c.640G>A, c.1268C>T, c.1207dupG) and likely pathogenic (c.766C>T) variants in the NDUFV1 gene. We show the mutation c.766C>T associated with a childhood onset phenotype of hypotonia, muscle weakness, psychomotor regression, lethargy, dysphagia, and strabismus. Additionally, this mutation was found to be associated with headaches and exercise intolerance in adulthood. We also review reported pathogenic variants in NDUFV1 highlighting the wide phenotypic heterogeneity in CI deficiency.

Keywords:
Leigh Syndrome; mitochondrial diseases; metabolic acidosis; encephalomyopathies

Nucleotide change	Amino acid change	Clinical phenotype (age of onset)	Brain MRI	Het/Hom	Segregation	Ref
c.640G>A c.1207dupG	p.Glu214Lys p.Asp403Gly^*fs	Developmental/cognitive delay, autistic behaviors, vomits, apnea (3 y/o)	Hyperintense signal in T2, hypointense in T1 affecting the central portions of the upper segment of the cervical spinal cord. Symmetric lesions affecting the mesencephalon, bridge, bulb, cerebellum. Lactate peak	C. het	Mat. c.640G>A Pat. c.1207dupG	Present Report
c.1268C>T	p.Thr423Met	Cervical hypotonia, right hypertonia, lethargy, apnea (1 y/o) Optic atrophy, sensorineuronal deafness, ptosis, global hypotonia, hyperreflexia with diplegic spasticity, dysphagia and hyperhidrosis (11 y/o)	Hyperintensity in T2/FLAIR in thalamus, lentiform nucleus, frontal lobe, corpus callosum knee. Lactate peak	Hom	Both	Present Report
c.1268C>T c.766C>T	p.Thr423Met p.Arg256Cys	Hypotonia, lethargy, motor regression and dysphagia (10 m/o), neurodevelopmental delay and strabismus (2 y/o)	Diffuse white matter lesions and lactate peak	C. het	Mat. c.1268C>T Pat. c.766C>T	Present Report
c.766C>T	p.Arg256Cys	Infant seizures, exercise intolerance and frequent headaches (adulthood)	N/A	Het	N/A	Present Report
c.1268C>T	p.Thr423Met	Myopathy, depression, fatigue (infancy)	Normal	Het	Maternal	*Baertling et al., 2018*Baertling F, Sánchez-Caballero L, van den Brand MAM, Distelmaier F, Janssen MCH, Rodenburg RJT, Smeitink JAM and Nijtmans LGJ (2018) A heterozygous NDUFV1 variant aggravates mitochondrial complex i deficiency in a family with a homoplasmic ND1 variant. J Pediatr 196:309-313.
c.1268C>T	p.Thr423Met	Horizontal nystagmus, dysarthria, bilateral dysmetria and intention tremor, dysdiadochokinesia, and gait ataxia (10 y/o)	Bilateral, symmetric, hyperintense signal in the putamen and right caudate nucleus on T2-weighted imaging and a high lactate peak in the affected areas	Hom	Both	*Incecik et al., 2018*Incecik F, Herguner OM, Besen S, Bozdoǧan ST and Mungan NO (2018) Late-onset Leigh syndrome due to NDUFV1 mutation in a 10-year-old boy initially presenting with ataxia. J Pediatr Neurosci 13:205-207.
c.1118T > C	p.Phe73Ser	CI deficiency symptoms N/D (6 m/o)	N/D	Hom	Both	*Srivasta et al., 2018*Srivastava A, Srivastava KR, Hebbar M, Galada C, Kadavigrere R, Su F, Cao X, Chnnaivan AM, Girisha KM, Shukla A et al. (2018) Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency. Eur J Hum Genet 26:1582-1587
c.1156C>T	p.Arg386Cys	Neuroregression, mild cognitive decline with regressive speech deficiencies, bilateral optic atrophy, and marked motor decline (6 y/o)	Diffuse white matter demyelination with cystic areas consistent with neurodegeneration	Hom	Both	*Srivasta et al., 2018*Srivastava A, Srivastava KR, Hebbar M, Galada C, Kadavigrere R, Su F, Cao X, Chnnaivan AM, Girisha KM, Shukla A et al. (2018) Genetic diversity of NDUFV1-dependent mitochondrial complex I deficiency. Eur J Hum Genet 26:1582-1587
c.1156C>T c.155+1G>G/A	p.Arg386Cys	Spasticity of all four limbs, brisk deep tendon reflexes and extensor plantar response, Ophthalmic evaluation revealed bilateral horizontal nystagmus with normal optic disc (1 y/o)	Diffuse cystic leukoencephalopathy involving corpus callosum, deep and periventricular white matter with sparing of basal ganglia, brainstem, and cerebellum	C. het	N/D	*Wadhwa et al., 2018*Wadhwa Y, Rohilla S and Kaushik JS (2018) Cystic Leucoencephalopathy in NDUFV1 Mutation. Indian J Pediatr 85:1128-1131.
c.605C>T c.816T>G	p.Ala202Val p.His272Gln	Dystonia, increased muscle tension, MR, left ventricular high voltage (21 m/o)	abnormal signals in bilateral Basal ganglia, brain stem and thalamus	C. het	Mat c.605C>T Pat.c.816T>G	*Fang et al., 2017*Fang F, Liu Z, Fang H, Wu J, Shen D, Sun S, Ding C, Han T, Wu Y, Lv J et al. (2017) The clinical and genetic characteristics in children with mitochondrial disease in China. Sci China Life Sci 60:746-757
c.1162+4A>C c.640G>A	p.Gly214Lys	Seizures, ptosis, scoliosis, dystonia, (2 y/o)	Symmetrical putaminal lesions, lactate peak, involvement of the left, body of the caudate and the right quadrigeminal plate	C. het	Pat. c.1162+4A>C Mat. c.640G>A	*Nafisinia et al., 2016*Nafisinia M, Guo Y and Dang X (2016) Whole Exome Sequencing Identifies the Genetic Basis of Late-Onset Leigh Syndrome in a Patient with MRI but little biochemical evidence of a mitochondrial disorder. JIMD Rep 32:117-124
c.365C>T c.158T>C	p.Pro122Leu p.Leu53Pro	Progressive weakness, epileptic seizures, optic atrophy, nystagmus, energy deficiency intolerance, learning disability (6 m/o)	white matter changes with leukomalacia and thinning of the corpus callosum, sparing the basal ganglia	C. het	Mat. c.365C>T Pat. c.158T>C	*Bjorkman et al., 2015*Björkman K, Sofou K, Darin N, Holme E, Kollberg G, Asin-Cayuela J, Dahle KMH, Oldfors A, Moslemi AR and Tulinius M (2015) Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1. Mitochondrion 21:33-40
c.365C>T c.158T>C	p.Pro122Leu p.Leu53Pro	Irritability, progressive weakness, epileptic seizures, optic atrophy, strabismus, energy deficiency intolerance, learning disability (7 m/o)	progressive white matter changes with cystic malacic degeneration	C. het	Mat. c.365C>T Pat. c.158T>C	*Bjorkman et al., 2015*Björkman K, Sofou K, Darin N, Holme E, Kollberg G, Asin-Cayuela J, Dahle KMH, Oldfors A, Moslemi AR and Tulinius M (2015) Broad phenotypic variability in patients with complex I deficiency due to mutations in NDUFS1 and NDUFV1. Mitochondrion 21:33-40
c.1156C>T c.914-8G_947	p.Arg386Cys	Inability to sit, poor head control, spasticity, brisk reflexes, sustained clonus, strabismus and nystagmus (1 y/o)	extensive atrophy of the white matter	C. het	Pat.r c.1156C>T Mat. c.914-8G_947	*Recalde et al., 2013*Recalde O, Fonseca DJ, Patiño LC, Atuesta JJ, Riveira-Nieto C, Restrepo CM, Mateus HE, van der Knaap MS and Laissue P (2013) A novel familial case of diffuse leukodystrophy related to NDUFV1 compound heterozygous mutations. Mitochondrion 13:749-754.
c.1156C>T	p.Arg386Cys	Mild titubation, drooling, increased irritability, axial hypotonia, lower extremity hypertonia, diffusely brisk reflexes and an extensor plantar response bilaterally with gait ataxia and frequent falls (14 m/o)	Bilateral symmetric hyperintense signal on T2-weighted imaging in periventricular white matter, centrum semiovale, corpus callosum, substantia nigra and periaqueductal gray associated with cystic necrosis, with a high lactate peak, decreased N-acetylaspartic acid (NAA) peak and increased choline peak	Hom	Both	*Marin et al., 2013*Marin SE, Mesterman R, Robinson B, Rodenburg RJ, Smeitink J and Tarnopolsky MA (2013) Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2. Gene 516:162-167
c.1156C>T	p.Arg386Cys	Developmental regression with intercurrent illness, left eye esotropia, dysphagia , ataxia, left hemi-body dystonic posturing, generalized spasticity, diffusely brisk reflexes, and extensor plantar responses (1 y/o)	N/D	Hom	Both	*Marin et al., 2013*Marin SE, Mesterman R, Robinson B, Rodenburg RJ, Smeitink J and Tarnopolsky MA (2013) Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2. Gene 516:162-167
c.262C>G c.596G>C	p.Arg88Gly p.Arg199Pro	Hypotonia, decreased spontaneous movements and hyperreflexia in the left lower extremity (32 m/o)	Symmetrical restricted diffusion of the corticospinal tracts and a lactate peak on MRS in the basal ganglia, thalamus and cortex	C. het	N/D	*Marin et al., 2013*Marin SE, Mesterman R, Robinson B, Rodenburg RJ, Smeitink J and Tarnopolsky MA (2013) Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2. Gene 516:162-167
c.1156C>T c.753delCCCC	p.Arg386Cys p.Ser251Ser^*fs	Becoming non-verbal, unable to sit, irritability, horizontal nystagmus, dysphagia, tremor, upper extremity weakness, axial hypotonia with appendicular hypertonia, hyperreflexia, and extensor plantar responses bilaterally (14.5 m/o) Decreased visual acuity, dysphagia and complex partial seizures (7 y/o)	MRIs initially showed an improvement in the white matter signal changes and new areas of restricted diffusion within the frontal lobes but later revealed increases in the abnormal whitematter signals with newinvolvement of the basal ganglia, diffuse cystic change and an elevated lactate peak in the basal ganglia	C. het	N/D	*Marin et al., 2013*Marin SE, Mesterman R, Robinson B, Rodenburg RJ, Smeitink J and Tarnopolsky MA (2013) Leigh syndrome associated with mitochondrial complex I deficiency due to novel mutations In NDUFV1 and NDUFS2. Gene 516:162-167
c.G1156A	p.Arg386His	Recurrent vomiting, dysphagia and fail- ure to thrive, axial hypotonia, tetraparesis without mus- cle wasting, irritability, and a rotatory nystagmus. hypoventilation of increasing intensity and rapid neurologic degradation (3.5 m/o)	T2 hypersig- nal and T1 hyposignal in the posterior part of the medulla, the pons and in the mesencephalon	Hom	Both	*Vilain et al., 2012*Vilain C, Rens C, Aeby A, Balériaux D, Bogaert PV, Remiche G, Smet J, Coster RV, Abramowicz M, Pirson I. (2012) A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome. Clinical Genetics. 82:264–270.
c.G1156A	p.Arg386His	rotatory nystagmus and mild peripheral hypotonia, Feeding difficulties and res- piratory insufficiency (3.5 m/o)	discrete symmetric T2 hyper- signal and T1 hyposignal lesions in the pons and the medulla	Hom	Both	*Vilain et al., 2012*Vilain C, Rens C, Aeby A, Balériaux D, Bogaert PV, Remiche G, Smet J, Coster RV, Abramowicz M, Pirson I. (2012) A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome. Clinical Genetics. 82:264–270.
c.770G>A c.632T>C	p.Arg257Gln p.Ala211Val	Regression in motor milestones stopped crawling and sitting independently (9 m/o)	Periventricular white matter abnormalities with sparing of the subcortical white matter	C. het	N/D	*Zafeiriou et al., 2008*Zafeiriou DI, Rodenburg RJT, Scheffer H, van der Heuvel LP, Pouwels PJW, Ververi A, Athanasiadou-Piperopoulou F and van der Knaap MS (2008) MR spectroscopy and serial magnetic resonance imaging in a patient with mitochondrial cystic leukoencephalopathy due to complex I deficiency and NDUFV1 mutations and mild clinical course. Neuropediatrics 39:172-175
c.640G>A c.1192+4A>C	p.Glu214Lys	Seizures (1 y/o), Cerebellar ataxia, psychomotor regression, strabismus and ptosis (28 m/o)	Brain atrophy and multiple symetric areas of hyperintensity in brain stem	C. het	Pat. c.640G>A Mat. c.1192+4A>C	*Benit et al., 2001*Bénit P, Chretien D, Kadhom N, Cormier-Daire V, Cabral A, Peudenier S, Rustin P, Munnich A and Rötig A (2001) Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am J Hum Genet 68:1344-1352.
c.1294G>C	Ala432Pro	Vomiting, hypotonia, lethargy and apnea (6 m/o)	areas of hyperintensity in the basal ganglia.	C. het	Pat. c.1294G>C Mat. c.990_991del	*Benit et al., 2001*Bénit P, Chretien D, Kadhom N, Cormier-Daire V, Cabral A, Peudenier S, Rustin P, Munnich A and Rötig A (2001) Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am J Hum Genet 68:1344-1352.
c.611A>G c.616T>G	p.Tyr204Cys p.Cys206Gly	Hypotonia, unable to sit, ataxia, bilateral ptosis and ophthalmoplegia (5 m/o)	areas of hyperintensity of the locus niger	C. het	Pat. c.611A>G Mat. c.616T>G	*Benit et al., 2001*Bénit P, Chretien D, Kadhom N, Cormier-Daire V, Cabral A, Peudenier S, Rustin P, Munnich A and Rötig A (2001) Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency. Am J Hum Genet 68:1344-1352.
c.175C>T c.1268C>T	p.Arg59X p.Thr423Met	Strabismus, progressive muscular hypotonia, myoclonic epilepsy and psychomotor regression. (5 m/o.)	cranial MRIs nor post-mortem reports were available to confirm symmetric midbrain or brainstem necrosis to definitively confirm Leigh syndrome	C. het	Pat. c.175C>T Mat. c.1268C>T	*Schuelke et al., 1999*Schuelke M, Smeitink J, Mariman E, Trijbels F, Stöckler-Ipsiroglu S and van den Heuvel L (1999) Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat Genet 21:260-261
c.1022C>T	Ala341Val	infantile myoclonic epilepsy, spasticity (6 m/o)	brain atrophy and a progressive macrocystic leukodystrophy	Hom	Both	*Schuelke et al., 1999*Schuelke M, Smeitink J, Mariman E, Trijbels F, Stöckler-Ipsiroglu S and van den Heuvel L (1999) Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat Genet 21:260-261
c.1118C>T	p.Phe373Ser	Seizures, myopia, bilateral lower set ears, nystagmus, mosaic pigmentary anomalies, hepatomegaly, and spasticity in lower limbs, extreme plantar responses and brisk deep tendon reflexes (6 m/o)	diffuse hyperintensity in the cerebral white matter, cerebellar white matter and brainstem white matter, and small cystic areas in the periventricular white matter	Hom	Both	*Schuelke et al., 1999*Schuelke M, Smeitink J, Mariman E, Trijbels F, Stöckler-Ipsiroglu S and van den Heuvel L (1999) Mutant NDUFV1 subunit of mitochondrial complex I causes leukodystrophy and myoclonic epilepsy. Nat Genet 21:260-261

Patient	Location (Chromossome 11)	Variant NM_007103.4	Zygosity	*Classification (ACMG)*	Inheritance
P1	67377981	c.640G>A (p.Glu214Lys)	Heterozygous	Pathogenic (PS1+PM1+PM2+PM3)	Maternal
P1	67379629	c.1207dupG (p.Asp403Glyfs^*27)	Heterozygous	Pathogenic (PVS1+PM2+PM3)	Paternal
P2	67379696	c.1268C>T (p.Thr423Met)	Homozygous	Pathogenic (PS1+PS3+PM2)	Both
P3	67379696	c.1268C>T (p.Thr423Met)	Comp. Heterozygous	Pathogenic (PS1+PS3+PM2)	Maternal
P3	67378531	c.766C>T (p.Arg256Cys)	Comp. Heterozygous	Likely Pathogenic (PM2+PM3+PP3+PP4)	Paternal

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[1] Send correspondence to Vanessa Zanette. Universidade Federal do Paraná, Departamento de Genética, Laboratório de Polimorfismos e Ligação, Av. Cel. Francisco H. dos Santos 100, 81530-000, Curitiba, PR, Brazil. E-mail: vanessa.bioinfo@gmail.com.