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Analysis of COQ2 gene in multiple system atrophy.

Ogaki K, Fujioka S, Heckman MG, Rayaprolu S, Soto-Ortolaza AI, Labbé C, Walton RL, Lorenzo-Betancor O, Wang X, Asmann Y, Rademakers R, Graff-Radford N, Uitti R, Cheshire WP, Wszolek ZK, Dickson DW, Ross OA - Mol Neurodegener (2014)

Bottom Line: Loss of function COQ2 mutations results in primary CoQ10 deficiency.We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients.Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ross.owen@mayo.edu.

ABSTRACT

Background: Loss of function COQ2 mutations results in primary CoQ10 deficiency. Recently, recessive mutations of the COQ2 gene have been identified in two unrelated Japanese families with multiple system atrophy (MSA). It has also been proposed that specific heterozygous variants in the COQ2 gene may confer susceptibility to sporadic MSA. To assess the frequency of COQ2 variants in patients with MSA, we sequenced the entire coding region and investigated all exonic copy number variants of the COQ2 gene in 97 pathologically-confirmed and 58 clinically-diagnosed MSA patients from the United States.

Results: We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients. In two patients, we identified two heterozygous COQ2 variants (p.S54W and c.403 + 10G > T) of unknown significance, which were not observed in 360 control subjects. We also identified one heterozygous carrier of a known loss of function p.S146N substitution in a severe MSA-C pathologically-confirmed patient.

Conclusions: The COQ2 p.S146N substitution has been previously reported as a pathogenic mutation in primary CoQ10 deficiency (including infantile multisystem disorder) in a recessive manner. This variant is the third primary CoQ10 deficiency mutation observed in an MSA case (p.R387X and p.R197H). Therefore it is possible that in the heterozygous state it may increase susceptibility to MSA. Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA.

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Macroscopic features and α-synuclein pathology of a patient with heterozygous COQ2 p.S146N variant (A-H). The infratentorial tissues were remarkable for severe atrophy of the pontine base and the inferior olive (A). The trigeminal nerve was unusually prominent due to the extreme pontine atrophy (arrows). Horizontal sections of the midbrain were remarkable for extremely marked atrophy (B). The substantia nigra had loss of pigmentation. The cerebrum peduncle was severely atrophic (B, arrowheads). Immunohistochemical staining for α-synuclein (LB509, mouse monoclonal; 1:100) in the globuls pallidus (C), putamen (D), substantia nigra (E), pontine nucleus (F), inferior olive (G) and the cerebellar white matter (H) (magnification × 400).
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Fig2: Macroscopic features and α-synuclein pathology of a patient with heterozygous COQ2 p.S146N variant (A-H). The infratentorial tissues were remarkable for severe atrophy of the pontine base and the inferior olive (A). The trigeminal nerve was unusually prominent due to the extreme pontine atrophy (arrows). Horizontal sections of the midbrain were remarkable for extremely marked atrophy (B). The substantia nigra had loss of pigmentation. The cerebrum peduncle was severely atrophic (B, arrowheads). Immunohistochemical staining for α-synuclein (LB509, mouse monoclonal; 1:100) in the globuls pallidus (C), putamen (D), substantia nigra (E), pontine nucleus (F), inferior olive (G) and the cerebellar white matter (H) (magnification × 400).

Mentions: This patient was a Caucasian male who had been clinically diagnosed with MSA-C (cerebellar variant of MSA) during his life. There is no family history of any similar disorder or other neurological disorders. His initial symptoms were staggering gait and frequent falls at the age of 54 years. A brain MRI showed marked atrophy of the pontine and cerebellar vermis at the age of 55 years. He had deterioration of his coordination, with not only worsening of his gait but also of his limbs and speech difficulties. Autonomic dysfunction included difficulty emptying the bladder, necessitating self-catheterization. Other autonomic dysfunction was otherwise suggested by several syncopal episodes. He was wheelchair bound at the age of 60 years. Muscle strength was normal. Deep tendon reflex were abnormally brisk at all sites and bilateral Babinski sign was positive. Severe ataxia was seen on finger to nose to finger test and heel-knee-shin testing. His treatment was limited to speech and physical therapy. He died of septicemia at the age of 68 years.He had an autopsy examination (Figure 2). The fixed tissue of the case weighted 680 grams and the calculated brain weight was 1360 grams. The infratentorial tissues were remarkable for severe atrophy of the pontine base and the inferior olive (Figure 2A). Horizontal sections of the midbrain, pons and medullar were remarkable for extremely marked atrophy. The substantia nigra had loss of pigmentation. The cerebrum peduncle was severely atrophic (Figure 2B, arrowheads). Microscopic analysis showed the neocortex was unremarkable in most areas. The pontine base and the inferior olive had severe neuronal loss and gliosis. In addition there were GCIs (Figure 2F & G). The cerebellum had severe diffuse loss of Purkinje cells with many axonal torpedoes. The internal granular cell layer had diffuse depopulation. The deep cerebellar white matter was markedly attenuated and gliotic with GCIs (Figure 2H). The pathological findings were of MSA (striatonigral and olivopontocerebellar degeneration), though the degree of the α-synuclein pathology was more severe than for typical MSA cases.Figure 2


Analysis of COQ2 gene in multiple system atrophy.

Ogaki K, Fujioka S, Heckman MG, Rayaprolu S, Soto-Ortolaza AI, Labbé C, Walton RL, Lorenzo-Betancor O, Wang X, Asmann Y, Rademakers R, Graff-Radford N, Uitti R, Cheshire WP, Wszolek ZK, Dickson DW, Ross OA - Mol Neurodegener (2014)

Macroscopic features and α-synuclein pathology of a patient with heterozygous COQ2 p.S146N variant (A-H). The infratentorial tissues were remarkable for severe atrophy of the pontine base and the inferior olive (A). The trigeminal nerve was unusually prominent due to the extreme pontine atrophy (arrows). Horizontal sections of the midbrain were remarkable for extremely marked atrophy (B). The substantia nigra had loss of pigmentation. The cerebrum peduncle was severely atrophic (B, arrowheads). Immunohistochemical staining for α-synuclein (LB509, mouse monoclonal; 1:100) in the globuls pallidus (C), putamen (D), substantia nigra (E), pontine nucleus (F), inferior olive (G) and the cerebellar white matter (H) (magnification × 400).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4233093&req=5

Fig2: Macroscopic features and α-synuclein pathology of a patient with heterozygous COQ2 p.S146N variant (A-H). The infratentorial tissues were remarkable for severe atrophy of the pontine base and the inferior olive (A). The trigeminal nerve was unusually prominent due to the extreme pontine atrophy (arrows). Horizontal sections of the midbrain were remarkable for extremely marked atrophy (B). The substantia nigra had loss of pigmentation. The cerebrum peduncle was severely atrophic (B, arrowheads). Immunohistochemical staining for α-synuclein (LB509, mouse monoclonal; 1:100) in the globuls pallidus (C), putamen (D), substantia nigra (E), pontine nucleus (F), inferior olive (G) and the cerebellar white matter (H) (magnification × 400).
Mentions: This patient was a Caucasian male who had been clinically diagnosed with MSA-C (cerebellar variant of MSA) during his life. There is no family history of any similar disorder or other neurological disorders. His initial symptoms were staggering gait and frequent falls at the age of 54 years. A brain MRI showed marked atrophy of the pontine and cerebellar vermis at the age of 55 years. He had deterioration of his coordination, with not only worsening of his gait but also of his limbs and speech difficulties. Autonomic dysfunction included difficulty emptying the bladder, necessitating self-catheterization. Other autonomic dysfunction was otherwise suggested by several syncopal episodes. He was wheelchair bound at the age of 60 years. Muscle strength was normal. Deep tendon reflex were abnormally brisk at all sites and bilateral Babinski sign was positive. Severe ataxia was seen on finger to nose to finger test and heel-knee-shin testing. His treatment was limited to speech and physical therapy. He died of septicemia at the age of 68 years.He had an autopsy examination (Figure 2). The fixed tissue of the case weighted 680 grams and the calculated brain weight was 1360 grams. The infratentorial tissues were remarkable for severe atrophy of the pontine base and the inferior olive (Figure 2A). Horizontal sections of the midbrain, pons and medullar were remarkable for extremely marked atrophy. The substantia nigra had loss of pigmentation. The cerebrum peduncle was severely atrophic (Figure 2B, arrowheads). Microscopic analysis showed the neocortex was unremarkable in most areas. The pontine base and the inferior olive had severe neuronal loss and gliosis. In addition there were GCIs (Figure 2F & G). The cerebellum had severe diffuse loss of Purkinje cells with many axonal torpedoes. The internal granular cell layer had diffuse depopulation. The deep cerebellar white matter was markedly attenuated and gliotic with GCIs (Figure 2H). The pathological findings were of MSA (striatonigral and olivopontocerebellar degeneration), though the degree of the α-synuclein pathology was more severe than for typical MSA cases.Figure 2

Bottom Line: Loss of function COQ2 mutations results in primary CoQ10 deficiency.We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients.Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. ross.owen@mayo.edu.

ABSTRACT

Background: Loss of function COQ2 mutations results in primary CoQ10 deficiency. Recently, recessive mutations of the COQ2 gene have been identified in two unrelated Japanese families with multiple system atrophy (MSA). It has also been proposed that specific heterozygous variants in the COQ2 gene may confer susceptibility to sporadic MSA. To assess the frequency of COQ2 variants in patients with MSA, we sequenced the entire coding region and investigated all exonic copy number variants of the COQ2 gene in 97 pathologically-confirmed and 58 clinically-diagnosed MSA patients from the United States.

Results: We did not find any homozygous or compound heterozygous pathogenic COQ2 mutations including deletion or multiplication within our series of MSA patients. In two patients, we identified two heterozygous COQ2 variants (p.S54W and c.403 + 10G > T) of unknown significance, which were not observed in 360 control subjects. We also identified one heterozygous carrier of a known loss of function p.S146N substitution in a severe MSA-C pathologically-confirmed patient.

Conclusions: The COQ2 p.S146N substitution has been previously reported as a pathogenic mutation in primary CoQ10 deficiency (including infantile multisystem disorder) in a recessive manner. This variant is the third primary CoQ10 deficiency mutation observed in an MSA case (p.R387X and p.R197H). Therefore it is possible that in the heterozygous state it may increase susceptibility to MSA. Further studies, including reassessing family history in patients of primary CoQ10 deficiency for the possible occurrence of MSA, are now warranted to resolve the role of COQ2 variation in MSA.

Show MeSH
Related in: MedlinePlus